Foamable compositions, breakable foams and their uses

ABSTRACT

A substantially surface active agent-free foamable composition which includes short-chain alcohol, water, polymer, fatty alcohol or fatty acid or a combination of fatty alcohol and fatty acid and propellant. A substantially surface active agent-free foamable composition which includes, water, polymer, fatty alcohol or fatty acid and propellant. A method of treatment using a substantially surface active agent-free foamable compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/359,709, filed Jan. 27, 2012, which is a continuation ofInternational Application No. PCT/IB10/02241, filed Jul. 29, 2010, whichclaims the benefit of U.S. Provisional Application No. 61/229,332 filedJul. 29, 2009, the contents of all of which are hereby incorporated byreference in their entireties herein.

BACKGROUND

Foam compositions with high amounts of alcohol are known in the art.Alcohol-based compositions are useful because of the anti-microbialproperties of alcohol and the ability for alcohol to dissolve certainactive agents.

Foams and, in particular, single-phase foams are complicated systemswhich do not form under all circumstances. Slight shifts in foamcomposition, such as by the addition of active ingredients or theremoval of any of the essential ingredients, may destabilize the foam.

The prior art teaches hydro-alcoholic foam compositions requiresignificant amounts of short-chain alcohols (namely, ethanol, propanol,isopropanol, butanol, iso-butanol, t-butanol and pentanol), water, fattyalcohols, polymer and surfactant to form a foam. These compositionsrequire various surfactants, such as, non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and ampholytic surfactants, asessential components.

Surfactants are known as essential ingredients in foam compositionsbecause of their amphiphilic properties and because they are consideredessential in forming a foam. However, many surfactants are known to beirritating when left on the skin, as they can extract lipids from theskin, thereby damaging skin barrier and exposing the skin to contactwith pro-inflammatory factors. (See, Dermatitis, Vol. 33(4) 217-225, 11Apr. 2006, John Wiley & Sons).

Lower alcohols are defatting agents. They are known to extract skinfats, thereby disrupting skin barrier function and causing irritation.They are known to cause skin to become dry and cracked (See, forexample, Industrial Guide to Chemical and Drug Safety, by T. S. S.Dikshith, Prakash V. Diwan, John Wiley & Sons, Inc., 2003, p. 228-9).

Thus the combination of a short chain alcohol and a surfactant can havea doubly undesirable irritating and defatting effect, as well as thedrawback of enhanced delivery of drugs through the skin, which resultsin increased systemic exposure (which is undesirable for topicaltreatment of the skin).

Hydro-alcoholic foams, as described in the prior art are inherentlythermally unstable, and they will collapse upon exposure to the skin andbody (at temperatures around 37° C.). They are therefore commonly termed“quick breaking” foams. Typically, when a quick breaking foam is appliedto fingers (as is usually done in order to apply a drug to a targetarea), it melts and rapidly (on exposure to body temperature of about37° C.) and collapses leaving behind a small pool of liquid. The thermalinstability of the foam makes it difficult to apply to a large targetarea by first administering the foam to the hands and then spreading thefoam onto the affected area.

SUMMARY

The present application relates to foamable formulations and foams andtheir uses comprising, short chain alcohols (“SCA's”), and especiallyethanol. In one or more embodiments the short chain alcohol is ethanol.In one or more embodiments the short chain alcohol is isopropanol. Inone or more embodiments the SCA's are needed as part of a drug carrier.For example certain drugs require alcohol in order to solubilize them.In one or more other embodiments, the SCA's are provided to facilitateor enhance the transdermal penetration or delivery of a drug. In one ormore additional cases, the SCA's are provided to have a defatting effectat the target site, for example where the site of treatment is oily andthe defatting effect of alcohol is desirable.

Unexpectedly, it has been discovered that quality hydro-alcoholicfoamable formulations and foams can be achieved, which upon dispensingare thermally stable, for example, as shown by having a collapse time ofabout 60 seconds or more at 36° C., and yet are easily breakable uponapplication of shear force, without the presence of significant amountsof standard surface active agents known in the art. In other wordscontrary to the prior art these foams do not collapse rapidly onexposure to body temperature but remain stable for a sufficient periodof time so that they can be conveniently applied to a target sitewithout having to take special precautions, such as only applying thefoam to a cold surface. Thus, in one or more embodiments, there isprovided a substantially surfactant free hydro-alcoholic foamableformulation or foam. In one or more preferred embodiments thehydro-alcoholic formulations and foams are free of surface activeagents. Moreover, it has been further discovered that these formulationsand foams can be achieved over a large range of alcohol content. Thus,for certain delivery systems there is provided a surfactant-freefoamable composition and foam, comprising about a medium level to abouta very high level of content of a short-chain alcohol.

In one or more embodiments there is provided a safe and effectivefoamable carrier composition and foam comprising a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition, wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30 In one ormore other embodiments there is provided a safe and effective foamablepharmaceutical or cosmetic composition and foam comprising an effectiveamount of a pharmaceutical or cosmetic agent, a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition, wherein the percent by weight is based on weightfoamable composition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30. Thefoaming booster surprisingly does not need to include a surfactant; andcan include a polymeric agent and at least one fatty alcohol, or atleast one a fatty acid or a combination thereof or a synergisticcombination of two or more fatty alcohols. The SCA is present in asubstantial amount. By a substantial amount, it is meant that thealcohol is present at a % concentration by weight at which it is capableof having a defoaming effect and/or an irritating effect. In one or moreembodiments the alcohol is at least about 15% by weight. In otherembodiments it is at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, or at least about 60% by weight. Inone or more embodiments the SCA is at a concentration between about 15%to about 65% by weight, or about 20% to about 60% by weight, preferablybetween about 25% to about 55% by weight, and more preferably betweenabout 30% to about 50% by weight. The carrier and pharmaceuticalcomposition is substantially surfactant free and preferably does notcontain a surfactant.

In one or more embodiments there is provided a substantially surfactantfree foamable composition comprising a short chain alcohol, water, afoaming booster comprising a polymer and at least one fatty alcohol orat least one fatty acid or a combination thereof and a liquefied orcompressed gas propellant at a concentration of about 3% to about 30% byweight of the total composition. The percent by weight is based onweight foamable composition; wherein the ratio range of compositionother than propellant to propellant is from about 100:3 to about 100:30;and wherein upon dispensing the foamable carrier composition forms afoam of quality that is thermally stable at a temperature of 36° C.having a collapse time of about or more than 60 seconds.

In one or more embodiments there is provided a substantially surfactantfoamable composition comprising a short chain alcohol, water, a foamingbooster comprising a polymer and at least one fatty alcohol or at leastone fatty acid or a combination thereof or a synergistic combination oftwo or more fatty alcohols and a liquefied or compressed gas propellantat a concentration of about 3% to about 30% by weight of the totalcomposition; wherein the percent by weight is based on weight foamablecomposition; wherein the ratio range of composition other thanpropellant to propellant is from about 100:3 to about 100:30. In one ormore embodiments the ratio between a first fatty alcohol and a secondfatty alcohol is between about 11:5 and about 5:11. If there is morethan two the ratio between the first (having the highest concentration)and the remaining fatty alcohols is between about 2:1 and about 1:2.

In one or more embodiments there is provided a method of preventing orameliorating or eliminating or treating or alleviating a dermatologicalor mucosal disorder, comprising: applying a substantially surfactantfree foamable composition to a surface having a dermatological ormucosal disorder in need of treatment, said composition comprising ashort chain alcohol, water, a foaming booster comprising a polymer, atleast one fatty alcohol or at least one fatty acid or combinationthereof or a synergistic combination of two or more fatty alcohols and aliquefied or compressed gas propellant at a concentration of about 3% toabout 30% by weight of the total composition; wherein the percent byweight is based on weight foamable composition; wherein the ratio rangeof composition other than propellant to propellant is from about 100:3to about 100:30; and wherein upon dispensing the foamable carriercomposition forms a foam that is thermally stable at a temperature of36° C. having a collapse time of about or more than 60 seconds.

Unexpectedly, it has been further discovered that quality hydro foamableformulations and foams, which are substantially free of SCA, can beachieved without the presence of significant amounts of standard surfaceactive agents known in the art, by using the carrier discovered forhydro-alcoholic foams without the SCA. Thus, in one or more embodiments,there is provided a substantially surfactant free hydro foamableformulation or foam. In one or more preferred embodiments the hydroformulations and foams are free of surface active agents.

In one or more embodiments, the foamable formulation is clear andtransparent when pressurized by the propellant. In a further embodimentthe foamable formulation is clear and transparent prior to addition ofone or more active agents at which point it forms a homogenoussuspension of active agent. Yet, in certain other embodiments theformulation is a suspension prior to addition of propellant and remainsa suspension when pressurized by the propellant.

According to an embodiment the one or more active agents is selectedfrom the group consisting of active herbal extract, an acaricides, anage spot and keratose removing agent, an allergen, an alpha hydroxylacid, an analgesic agent, an anesthetic, an immunogenic substance, anantiacne agent, an antiallergic agent, an antiaging agent, anantibacterial agent, an antibiotic, an antiburn agent, an anticanceragent, an antidandruff agent, an antidepressant, an antidermatitisagent, an antiedemic anent, an antifungal agent, an antihistamine, anantihelminth agent, an antihyperkeratolyte agent, an anti-infectiveagent, an antiinflammatory agent, an antiirritant, an antilipemic agent,an antimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an anti-pigmentation agent, an antiproliferativeagent, an antipruritic agent, an antipsoriatic agent, an antirosaceaagent, an antiseborrheic agent, an antiseptic agent, an antiswellingagent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, anantiyeast agents, an astringent, a beta-hydroxy acid, benzoyl peroxide,benzoyl chloride a, topical cardiovascular agent, a chemotherapeuticagent, a corticosteroid, an immunogenic substance, a dicarboxylic acid,a disinfectant, a fungicide, a hair growth regulator, a haptene, ahormone, a hydroxy acid, an immunosuppressant, an immunoregulatingagent, an immunomodulator, an insecticide, an insect repellent, akeratolytic agent, a lactam, a local anesthetic agent, a lubricatingagent, a masking agent, a metals, a metal oxide, a mitocide, aneuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, silicone talc, a skin protective agent,a skin whitening agent, a steroid, a steroid hormone, a steroidalantiinflammatory agent ,a vasoconstrictor, a vasodilator, a vitamin, avitamin A, a vitamin A derivative, a vitamin B, a vitamin B derivative,a vitamin C, a vitamin C derivative, a vitamin D, a vitamin Dderivative, a vitamin D analog, a vitamin F, a vitamin F derivative, avitamin K, a vitamin K derivative, a wound healing agent and a wartremover and mixtures thereof

In a further embodiment the active agent is selected from the groupconsisting of mometasone furoate or betamethasone valerate, diclofenacsodium, metronidazole, benzoyl peroxide, minoxidil.

In an embodiment the composition comprises a fatty alcohol. The fattyalcohol can be a straight chain fatty alcohol, a saturated fattyalcohol, an unsaturated fatty alcohol, a hydroxyl substituted fattyalcohol or a branched fatty alcohol. In an embodiment the fatty alcoholis a therapeutically active fatty alcohol.

In additional embodiments, the foamable composition comprises a fattyacid. The fatty acid can be a straight chain fatty acid, a saturatedfatty acid, an unsaturated fatty acid, a hydroxyl fatty acid or abranched fatty acid. In an embodiment the fatty acid is atherapeutically active fatty acid.

According to additional embodiments there is provided a method ofproducing a foamable composition, including:

-   -   1. providing a foamable therapeutic composition including a        therapeutic agent at a therapeutically effective concentration,        a short chain alcohol, for example, at a concentration of about        20% to about 60% by weight, a hydroalcoholic composition foaming        booster (including at least one of a polymer, a fatty alcohol or        a fatty acid) and water    -   2. introducing the foamable composition in an aerosol packaging        assembly, comprising of a container, suitable for containing a        pressurized product and a valve, capable of extruding a foam;        and    -   3. introducing to the aerosol packaging assembly a liquefied or        compressed gas propellant at a concentration of about 3% to        about 30% by weight of the total composition.

In one or more certain embodiments the SCA content can be in excess of60%, or in excess of 65%, however, as the level reaches towards 70% itis harder to prepare a satisfactory formulation and higher levels ofhydro-alcoholic foam booster can be appropriate. In certaincircumstances having both fatty acid and fatty alcohol may help. Thegreater challenge to form hydro-alcoholic foamable formulations and foamwith very high levels of SCA's is presumably without being bound by anytheory because of the defoaming and thermolabile properties of thealcohol, the high level of alcohol and the lower level of water.

According to further embodiments there is provided a method ofpreventing, treating ameliorating or eliminating a disorder by selectingand releasing on to a convenient surface a safe and effectivepharmaceutical or cosmetic foamable composition comprising an effectiveamount of a pharmaceutical or cosmetic agent, a short chain alcohol(“SCA”), water, a foaming booster and a liquefied or compressed gaspropellant at a concentration of about 3% to about 30% by weight of thetotal composition; directing the released foam on to a target on apatient in need; applying a shear force to and spreading the foam overthe target surface such that after a simple rub the foam is no longervisible to the naked eye as it is absorbed rapidly on to the targetsurface.

According to one of more further embodiments the disorder treated by thefoamable composition is selected from the group consisting of adermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an analdisorder, a disorder of a body cavity, an ear disorder, a disorder ofthe nose, a disorder of the respiratory system, a bacterial infection, afungal infection, a viral infection, dermatosis, dermatitis, parasiticinfections, disorders of hair follicles and sebaceous glands, scalingpapular diseases, benign tumors, malignant tumors, reactions tosunlight, bullous diseases, pigmentation disorders, disorders ofcornification, pressure sores, disorders of sweating, inflammatoryreactions, xerosis, ichthyosis, an allergy, a burn, a wound, a cut, achlamydia infection, a gonorrhea infection, hepatitis B, herpes,HIV/AIDS, human papillomavirus (HPV), genital warts, bacterialvaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranlomavenereum, mucopurulent cervicitis (MPC), molluscum contagiosum,nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders,vulvodynia, vulvar pain, a yeast infection, vulvar dystrophy, vulvarintraepithelial neoplasia (VIN), contact dermatitis, osteoarthritis,joint pain, an hormonal disorder, a pelvic inflammation, endometritis,salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer ofthe vulva, cancer of the vagina, vaginal dryness, dyspareunia, an analand rectal disease, an anal abscess/fistula, anal cancer, an analfissure, an anal wart, Crohn's disease, hemorrhoids, anal itch, pruritusani, fecal incontinence, constipation, polyps of the colon and rectum.

DETAILED DESCRIPTION Foamable Composition and Foam Properties

The ability to achieve quality foam with a substantial concentration ofat least one short chain alcohol without a surfactant is surprising,because, such alcohols are not prone to creating a foam. The challengeis not just to achieve a quality foam but also to attain a formulationthat will satisfy a plurality of two, three, four, five, six or more ofthe following property specifications simultaneously.

-   -   1. Uniformity: The composition should be formulated so that it        is and can remain uniform without phase separation or        precipitation over time. This property is of high importance        when the product is intended to be a pharmaceutical product. In        some embodiments the formulation is shaken before use and is        readily re-homogenized upon shaking so the composition is        uniform when dispensed.    -   2. Flowability: The composition, when placed in an aerosol        container and pressurized should be flowable such that it can be        expelled through the canister valve. It should preferably also        be shakable inside the container. These requirements create a        formulation challenge, because low or non-viscous flowable and        shakable compositions are prone to undergo phase separation or        precipitation.    -   3. Quality: Upon release from the can, the composition should        generate a foam of good or excellent quality having low density        and small bubble size.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the foam coming out of the container is very        delicate: on one hand the foam should preferable not be “quick        breaking”, i.e., it should be at least short term stable upon        release from the pressurized container and not break as a result        of exposure to skin temperature; and on the other hand, it        should be “breakable”, i.e., it should spread easily, break down        and absorb into the skin or membrane upon application of mild        shear force.    -   5. Skin Feeling: To ensure patient compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimal    -   6. Non-irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should preferably be        eliminated from the composition or reduced as much as possible.    -   7. Delivery: Finally, the composition should also be designed to        ensure efficient delivery of a therapeutic agent into the target        site of treatment.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulations asdescribed below.

Compositions

All % values are provided on a weight (w/w) basis.

In one or more embodiments there is provided a foamable compositionincluding:

-   -   1. a short chain alcohol    -   2. a foaming booster, comprising        -   a. at least one fatty alcohol or at least one fatty acid or            a combination thereof or a synergistic combination of two or            more fatty alcohols; and/or        -   b. about 0.1% to about 5% by weight of at least one            polymeric agent selected from a bioadhesive agent, a gelling            agent, a film forming agent and a phase change agent;    -   3. water; and    -   4. a liquefied or compressed gas propellant.

In one or more other embodiments the fatty acid(s) and fatty alcohol(s)may combine to have a synergistic effect. In one or more furtherembodiments the fatty acid(s) and fatty acids(s) may combine to have asynergistic effect. In one or more embodiments the synergism is toimprove foam quality. In one or more other embodiments the synergism isto improve foam thermal stability. In one or more other embodiments thesynergism is to improve foam collapse time, which is can be an indicatorof thermal stability.

In one or more embodiments the foamable composition is substantiallysurfactant free. In one or more other embodiments it is essentiallysurfactant free, namely a non surfactant composition.

In one or more embodiments the foaming booster combination is asynergistic combination that can improve the foam quality and or thermalstability of the composition.

In one or more embodiments the short chain alcohol, is preferablyethanol. In one or more embodiments the short chain alcohol, ispreferably isopropanol. In one or more embodiments the short chainalcohol is at least about 15% by weight of the composition. In one ormore embodiments the short chain alcohol is at a concentration of about20% to about 60% by weight. In one or more embodiments the short chainalcohol is at a concentration of about 30% to about 60% by weight. Inone or more embodiments the short chain alcohol is at a concentration ofabout 40% to about 60% by weight. In one or more other embodiments theSCA is propanol or butanol or a branched chain derivative thereof suchas isopropanol or iso-butanol. In one or more embodiments it is apentanol.

Upon release from an aerosol container, the foamable composition formsan expanded breakable foam suitable for topical administration. In oneor more other embodiments the foam is a breakable foam that is thermallystable upon dispensing, for example, as selected by a collapse time ofabout 60 secs or more; and yet breaks easily upon application of shearforce.

The foamable composition is suitable for administration to various bodyareas, including, but not limited to the skin, a body surface, a bodycavity, a mucosal surface, e.g., the mucosa of the nose, mouth and eye,the ear, the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”)

According to one or more embodiments, the foamable composition furthercomprises a cosmetic or a pharmaceutical active agent (severally andinterchangeably termed herein “active agent”).

In one or more embodiments there is provided a foamable compositionincluding:

-   -   1. an active agent at an effective concentration;    -   2. a short chain alcohol, preferably ethanol, at a concentration        of about 20% to about 60% by weight;    -   3. at least one fatty alcohol or at least one fatty acid or a        combination thereof or a synergistic combination of two or more        fatty alcohols ;    -   4. about 0.1% to about 5% by weight of at least one polymeric        agent selected from a bioadhesive agent, a gelling agent, a film        forming agent and a phase change agent;    -   5. water; and    -   6. a liquefied or compressed gas propellant.

In one or more other embodiments the polymeric agent can be at aconcentration less than about 0.1% by weight of the formulation.

In one or more embodiments, at least a portion of the therapeutic agentis suspended or dissolved evenly throughout the entire composition.

In one or more embodiments, the foam composition is clear andtransparent when placed under the pressure of the propellant. In one ormore embodiments, the composition is transparent upon pressurization bythe gas propellant.

It has been discovered that formulations containing high amount of a SCA(such as ethanol) are not prone to foaming when using combinations ofdifferent types of surfactants and different types of polymers. Foamsproduced were not of quality and/ or collapsed rapidly. It was foundthat the combination of at least two suitable fatty alcohols (e.g.stearyl alcohol with cetyl alcohol or cetyl alcohol with myristylalcohol) or a combination of at least one fatty alcohol with at leastone fatty acid (e.g. stearyl alcohol with stearic acid) or thecombination of at least two suitable fatty acids (e.g. myristic acidwith stearic acid) produced good to excellent quality short term stablefoams in the absence of customary surfactants. It was further discoveredthat fatty alcohols or fatty acids with a saturated carbon chain ofbetween 14 to 18 carbons or between 16 to 18 carbons combined withcellulose-based polymers have outstanding foam boosting properties.Surprisingly it has also been discovered that at least two fattyalcohols or at least two fatty acids combined with cellulose-basedpolymers have outstanding foam boosting properties. These foam boostingcombinations provide breakable foams of good or excellent quality havingenhanced thermal stability at 36° C.

For example, it was found that when myristyl alcohol or cetyl alcoholwere used alone in hydro-alcoholic formulations, poor and fairly goodfoams were obtained respectively. Surprisingly however, when myristylalcohol was combined with cetyl alcohol at a 1:1 ratio, a short termstable breakable foam of good quality was obtained. Thus, thecombination of cetyl and myristyl alcohol combined with a polymericagent, has a synergistic foam boosting effect.

It was further found that when cetyl alcohol or stearyl alcohol wereused alone in hydro-alcoholic formulations combined with a polymericagent, fairly good and good foams were achieved respectively.Surprisingly however, when stearyl alcohol was combined with cetylalcohol at a 1:1 ratio, in a formulation containing a polymeric agent, ashort term stable breakable foam of excellent quality was obtained.Thus, the combination of cetyl and stearyl alcohol combined with apolymeric agent, has a synergistic foam boosting effect.

Furthermore when stearyl alcohol and stearic acid were each used alonewith a polymeric agent in hydro-alcoholic formulations or combined (at aratio of 1:1) good quality foams were obtained. A short term stablebreakable foam having a low density was obtained as a result of saidcombination.

Thus in one or more embodiments, there is provided a hydro-alcoholicfoamable formulation which provides a good to excellent breakable foam.In one or more embodiments the foam displays a collapse time of about 60sec or more, or of about 90 seconds or more, or of about 120 seconds ormore, or of about 150 seconds or more, or of about 180 seconds or moreat 36° C. In other words it displays a thermal stability on exposure toa body surface at normal body temperature.

In one or more embodiments the foam displays a collapse time of about 60seconds or less, or of about 50 seconds or more, or of about 40 secondsor more, or of about 30 seconds or more at 36° C. In one or more otherembodiments the foam displays a thermal liability on exposure to a bodysurface at normal body temperature.

In one or more embodiments the fatty acid or fatty alcohol has 14 to 22carbon atoms in its carbon chain. In one or more embodiments the fattyacid or fatty alcohol has 16 to 22 carbon atoms in its carbon chain.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation comprising fatty alcohols or fatty acids combined withcellulose-based polymers having outstanding foam boosting properties.

In one or more embodiments there is provided a foaming boostercomprising at least one fatty alcohol or at least one fatty acid or acombination thereof. In one or more embodiments the combination is asynergistic combination. In certain embodiments the synergism results inan improved foam quality. In certain embodiments the synergism resultsin a thermal stability or in an improved thermal stability. In certainembodiments the thermal stability is exhibited when the composition isplaced on a mammal at normal body temperature. In an embodiment themammal is a human.

In one or more other embodiments the foaming booster consistsessentially of at least one fatty alcohol or at least one fatty acid ora combination thereof. In one or more other embodiments the foamingbooster consists essentially of at least two fatty alcohols. In one ormore other embodiments the foaming booster consists essentially of atleast two fatty acids. In one or more other embodiments the foamingbooster is between about 1% and about 10% by weight of the composition.

In one or more embodiments the foamable formulation comprises asynergistic combination of two or more fatty alcohols to achieve a foamwith thermal stability. In one or more embodiments, the foamableformulation comprises a synergistic combination of two or more fattyacids to achieve a foam with thermal stability. In one or moreembodiments the foamable formulation comprises a synergistic combinationof at least one fatty acid and at least one fatty alcohol to achieve afoam with thermal stability. In one or more embodiments, the foamableformulation comprises a synergistic combination of two or more fattyalcohols or fatty acids or a fatty acid and fatty alcohol at a ratio ofabout 1:1. By about it is intended to provide for a variation of 35% orof 30% or of 25% or of 20% or of 10% or of 5% or of 1% or any % betweenany of these amounts. If there are more than two fatty alcohols then inone or more embodiments the ratio between a first fatty alcohol (havingthe highest concentration) and the remaining fatty alcohols is betweenabout 2:1 and about 1:2, or if there are more than two fatty acids thenin one or more embodiments the ratio between the first fatty acid(having the highest concentration) and the remaining fatty acids isbetween about 2:1 and about 1:2, or if there is a combination of fattyacids and fatty alcohols and there are more than one of one or both oftypes in one or more embodiments the ratio between the total fattyalcohols and the total fatty acids is between about 2:1 and about 1:2.In one or more further embodiments the aforesaid ratios are betweenabout 11:5 and about 5:11, or are in certain embodiments are about 1:1.

Furthermore, when stearic acid was used alone in hydro-alcoholicformulations, good quality foams were obtained. When stearic acid wascombined with myristic acid at a 1:1 ratio a short term breakable foamof good quality, having a low density was obtained.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation which provides a good breakable foam which has a collapsetime of at least about 60 sec at 36° C., and containing a combination oftwo or more fatty alcohols combined with a polymeric agent. In one ormore embodiments, there is provided a hydro-alcoholic foamableformulation which provides a breakable foam which is thermally stable asseen by having a collapse time of at least about 60 seconds or at leastabout 85 seconds or at least about 120 seconds; or at least about 180seconds at 36° C., and containing a combination of two or more fattyacids or a fatty acid with a fatty alcohol combined with a polymericagent.

In one or more other embodiments the fatty alcohol synergisticcombination is cetyl alcohol and myristyl alcohol. In one or more otherembodiments the fatty alcohol synergistic combination is stearyl alcoholand myristyl alcohol. In one or more other embodiments the fatty alcoholsynergistic combination is stearyl alcohol and cetyl alcohol. In one ormore embodiments, the ratio of fatty alcohols can be optimized in orderto obtain foams of good or excellent quality. In an embodiment the ratiobetween at least two fatty alcohols is about 1:1. In an embodiment theratio between at least of two fatty alcohols is between about 11:5 and5:11. In an embodiment the ratio between at least of two fatty alcoholsis between about 1:1 and 5:11.

In one or more other embodiments the foaming booster consistsessentially of at least one fatty alcohol or at least one fatty acid ora combination thereof combined with a polymeric agent. In one or moreother embodiments the foaming booster consists essentially of at leasttwo fatty alcohols. In one or more other embodiments the foaming boosterconsists essentially of at least two fatty acids.

Surprisingly, it appears that the foam quality can be influenced by theratio of mixtures of two or more fatty alcohols, such as cetyl andstearyl alcohol.

Formulations having a cetyl:stearyl alcohol ratio of about 1:1 to about5:11 generated, for example, a breakable foam of good to excellentquality being thermally stable on being applied to a surface at 36° C.having a collapse time of at least three minutes and having a lowdensity. When the ratio of cetyl:stearyl alcohol was about 11:5 goodquality foam was produced whereas, when the ratio about 1:1 to about5:11 a foam of excellent quality was produced.

Thus, in one or more embodiments, there is provided a hydro-alcoholicfoamable formulation of comprising about 11:5 to about 5:11cetyl:stearyl alcohol of good to excellent quality being thermallystable having a collapse time of at least a minute or at least twominutes or at least three minutes. In one or more embodiments, there isprovided a hydro-alcoholic foamable formulation of comprising about 11:5to about 5:11 cetyl:stearyl alcohol which generates a quality foam oflow density. In one or more embodiments, there is provided ahydro-alcoholic foamable formulation of good quality being thermallystable on being applied to a surface at 36° C. having a collapse time ofat least three minutes comprising a ratio of about 11:5 cetyl:stearylalcohol. In one or more embodiments, there is provided a hydro-alcoholicfoamable formulation of excellent quality being thermally stable onbeing applied to a surface at 36° C. having a collapse time of at leastthree minutes comprising a ratio of about 1:1 to about 5:11cetyl:stearyl alcohol.

The prior art hydroalcoholic foams are thermolabile and collapse quicklyon exposure to human body temperature. Interestingly, it wasunexpectedly discovered that surfactant contributed to thethermo-instability of hydroalcoholic foams. (Example 1 of U.S. Pat. No.6,126, 920)

It has further been discovered that removing the fatty alcohols fromquick breaking foam formulation (Example 1 of U.S. Pat. No. 6,126, 920)containing surfactants failed to produce a foam., whereas adding certainfatty alcohols (i.e. 3% cetostearyl alcohol) to this formulationimproved foam quality. These results collectively shows the importanceof excluding surface active agents and including suitable fatty alcoholsinto hydro-alcoholic foam formulations to produce quality breakablethermally stable foam. Thermally stable breakable foams of excellentquality were obtained in surfactant free formulations without humectantsand without pH buffering agents. However, the presence of a fattyalcohol combined with a polymer booster was required as formulationswith hydroxypropyl cellulose polymer but lacking cetostearyl alcoholfailed to produce foam.

In one or more embodiments there is provided a hydro-alcoholic foamformulation lacking a surface active agent and comprising polymer andsuitable fatty alcohols which produces quality breakable thermallystable foam. In one or more embodiments there is provided a surfactantfree hydro-alcoholic foam formulation comprising polymer and suitablefatty acids which produce quality breakable thermally stable foam. Inone or more embodiments there is provided a surfactant freehydro-alcoholic foam formulation comprising suitable fatty alcoholscombined with fatty acids ,which produce quality breakable thermallystable foam.

Furthermore, it was found that cellulose-based polymers (hydroxypropylmethylcellulose) have better foaming properties over pH sensitiveexpandable polymer like carbopol. In one or more embodiments there isprovided a hydro-alcoholic foam formulation comprising cellulose- basedpolymers.

Furthermore, the formulations of the present invention can provide foamsof excellent quality in the presence of various active ingredients.Extended accelerated stability of steroidal active ingredients, inhydro-alcoholic formulations of the present invention was demonstratedover a period of three and six months for betamethasone valerate and fora period of at least two months for mometasone furoate. Mometasonefuroate was soluble and produced clear, quality, thermally stableformulations.

In one or more embodiments there is provided a surfactant free stableshort term hydro-alcoholic foam formulation comprising at least oneactive ingredient. In one or more embodiments there is provided asurfactant free short term stable hydro-alcoholic foam formulationcomprising at least one steroidal active ingredient. In one or moreembodiments there is provided a surfactant free short terms stablehydro-alcoholic foam formulation comprising betamethasone valerate ormometasone furoate.

Formulations containing up to 60% ethanol provided thermally stablebreakable foams of good to excellent quality. Also surprisingly thecarrier without ethanol provided a good quality foam in the absence ofsurfactant. However, ethanol despite its defoaming and thermolabileproperties, unexpectedly improved the foam quality and generated stablebreakable foam contrary to that seen in the prior art. Foams of goodquality were produced also using isopropanol.

In one or more embodiments, there is provided a foamable formulation orbreakable foam of good quality having a low density and being thermallystable for more than one, or two or three minutes at 36° C. yetbreakable upon shear force comprising up to 60% ethanol. In one or moreembodiments, there is provided a foamable formulation or breakable foamof good quality comprising isopropanol. In one or more embodiments,there is provided a foamable formulation or breakable foam of goodquality comprising a carrier without ethanol provided a good qualityfoam in the absence of surfactant.

In one or more embodiments, there is provided a foamable formulationcomprising isopropanol that can generate a breakable foam of goodquality having a low density and being thermally stable by having acollapse time of about or more than one, or two or three minutes at 36°C. , and yet is breakable upon shear force.

Short Chain Alcohol

A short chain alcohol according to one or more certain otherembodiments, has up to 6 carbon atoms in their carbon chain skeleton andone hydroxy group. Such short chain alcohols can be selected fromethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol,pentanol and isomers thereof (herein after “a pentanol) and hexanol andisomers thereof (herein after “a hexanol). In a preferred embodiment theshort chain alcohol is ethanol. The SCA is present in a substantialamount. By a substantial amount is meant that the alcohol is present ata % concentration by weight at which it is capable of having a defoamingeffect and or an irritating effect. In various embodiments the amount ofshort chain alcohol is above about 10%. In one or more embodiments thealcohol is at least about 15% by weight. In other embodiments it is atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55%, or at least about 60% by weight. In one or moreembodiments the SCA is at a concentration between about 15% to about 65%by weight, or about 20% to about 60% by weight, preferably between about25% to about 55% by weight, and more preferably between about 30% toabout 50% by weight.

Fatty Alcohol

The hydro-alcoholic foamable composition foaming booster may include afatty alcohol. The fatty alcohol which acts as a foam adjuvant isincluded in the foamable compositions as a main constituent, to evolvethe foaming property of the composition and/or to stabilize the foam. Inone or more embodiments, the fatty alcohol is selected from the groupconsisting of fatty alcohols having 15 or more carbons in their carbonchain, such as cetyl alcohol and stearyl alcohol (or mixtures thereofi.e. cetostearyl having 1 ratio). Other examples of fatty alcohols aremyristyl alcohol (C14), arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). In one or more preferred embodiments, the fatty alcohol iscetyl alcohol, stearyl alcohol, behenyl alcohol or myristyl alcohol andcombinations thereof

Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are suitable as fatty alcohols in the context herein. Incertain embodiments the amount of the fatty alcohol required to supportthe foam system can be approximately inversely related to the length ofits carbon chains. Fatty alcohols are also useful in facilitatingimproved spreadability and absorption of the composition.

Fatty alcohols are amphiphatic, however unlike customary surfactants,they cannot usually function as stand-alone surfactants, because oftheir very weak emulsifying capacity. They are occasionally used asnon-ionic co-emulsifiers, i.e., and are commonly used as thickeners(Surfactants in personal care products and decorative cosmetics, byLinda D. Rhein, Mitchell Schlossman, Anthony O'Lenick, P., ThirdEdition, 2006, p. 247). Fatty alcohols are generally regarded as safeand they are not considered as irritants.

An important property of the fatty alcohols used in context of thecomposition disclosed herein is related to their therapeutic propertiesper se. Long chain saturated and mono unsaturated fatty alcohols, e.g.,stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol(docosanol) have been reported to possess antiviral, antiinfective,antiproliferative and anti-inflammatory properties (see, U.S. Pat. No.4,874,794). Longer chain fatty alcohols, e.g., tetracosanol,hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are alsoknown for their metabolism modifying properties and tissue energizingproperties.

The concentration of a fatty alcohol or a combination of different fattyalcohols in the composition can in one or more embodiments range betweenabout 0.1% and about 10% %, or between about 1% to about 15%. In certainembodiments, the concentration of the fatty acid can be selected fromthe group consisting of (i) between about 0.1% and about 1%, (ii)between about 1% and about 5%, and (iii) between about 5% and about 10%.In one or more embodiments, the fatty alcohol is at a concentration atabout 1% to about 3% by weight.

Fatty Acid

The hydro-alcoholic foamable composition foaming booster may include afatty acid or a combination of different fatty acids. In one or moreembodiments the fatty acid can have 16 or more carbons in its carbonchain, such as myristic acid (C14), hexadecanoic acid (C16) stearic acid(C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid(C28), as well as fatty acids with longer carbon chains (up to C50), ormixtures thereof

Optionally, the carbon atom chain of the fatty acid may have at leastone double bond; alternatively, the fatty acid can be a branched fattyacid. The carbon chain of the fatty acid also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid. In one or morepreferred embodiments, the fatty acid is hexadecanoic acid, stearic acidor behenic acid or myristic acid (C14), or combinations thereof

The fatty acid or combination of fatty acids according to one or moreembodiments can be included in the foamable composition in aconcentration of 0.1% to 5%. In one or more embodiments theconcentration of the combination of fatty acids in the composition canbe selected from the group consisting of (i) between about 0.1% byweight and about 1%, (ii) between about 1% by weight and about 5%, and(iii) between about 5% by weight and about 10%. In one or moreembodiments a combination of myristylic acid and stearic acid isprovided.

Fatty Acid Combined with Fatty Alcohol

In one or more embodiments, the hydro-alcoholic foamable compositionfoaming booster may include a combination at least one fatty acid withat least one fatty alcohol to provide a thermally stable breakable foam.In one or more embodiments a thermally stable breakable foam ofexcellent quality is obtained by combining stearyl alcohol with stearicacid.

Polymeric Agent (Polymer)

The hydro-alcoholic foamable composition foaming booster may include apolymeric agent. In one or more embodiments, the polymeric agentselected from the group consisting of a bioadhesive agent, a gellingagent, a film forming agent and a phase change agent. A polymeric agentenhances the creation of foam having fine bubble structure, which doesnot readily collapse upon release from the pressurized aerosol can. Thepolymeric agent serves to stabilize the foam composition and to controldrug residence in the target organ. In certain embodiments the polymercan have surfactant like properties and contribute to the stabilizationof emulsion formulations, such as poloxamer or pemulen (Acrylates/C10-30alkyl acrylate crosspolymer).

Exemplary polymeric agents include, in a non-limiting manner,naturally-occurring polymeric materials, such as locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum,sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guargum, cationic guars, hydroxypropyl guar gum, starch, amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid and hyaluronic acid; chemically modifiedstarches and the like, carboxyvinyl polymers, polyvinylpyrrolidone,polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acidpolymers, polyvinyl acetate polymers, polyvinyl chloride polymers,polyvinylidene chloride polymers and the like.

Additional exemplary polymeric agents include semi-synthetic polymericmaterials such as cellulose ethers, such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,carboxymethyl cellulose, carboxymethylcellulosecarboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer(homopolymer of acrylic acid is crosslinked with an allyl etherpentaerythritol, an allyl ether of sucrose, or an allyl ether ofpropylene, such as Carbopol® 934, Carbopol® 940, Carbopol® 941,Carbopol® 980 and Carbopol® 981. Poloxamers (synthetic block copolymerof ethylene oxide and propylene) such as Poloxamer 124, Poloxamer 188,Poloxamer 237, Poloxamer 338 and Poloxamer 407. Other useful Poloxamersare: 181, 182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 238, 331,333, 334, 335, 401, 402, and 403. Polyethylene glycol, having molecularweight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG10,000) also have gelling capacity and they are also consideredpolymeric agents.

In one or more embodiments the polymeric agent, used in the compositionis a cellulose-based polymer. In certain embodiments, it is selectedfrom the group consisting of hydroxypropyl methylcellulose orhydroxypropyl cellulose.

Mixtures of the above polymeric agents are contemplated.

The concentration of the polymeric agent should be selected so that thecomposition, after filling into aerosol canisters and pressurized withpropellant, is flowable, and can be shaken in the canister. In one ormore embodiments, the concentration of the polymeric agent is selectedsuch that the viscosity of the composition, prior to the filling of thecomposition into aerosol canisters, is less than 30,000 CP, and morepreferably, less than 15,000 CP.

Combination of a Fatty Alcohol and/or a Fatty Acid and a Polymeric Agent

When a polymeric agent alone is used, a foam of good quality is notobtained. When, however, a polymeric agent is combined with a fattyalcohol or a fatty acid (or a mixture of a fatty alcohol and fatty acid)these two components can, surprisingly, act to produce a good qualityfoam.

In one or more embodiments the range of ratio of fatty acid and or fattyalcohol to polymer can be about 100:1 to about 1:50; or about 90:1 toabout 1:45; or about 80:1 to about 1:40; or about 70:1 to about 1:35; orabout 60:1 to about 1:30; or about 50:1 to about 1:25; or about 40:1 toabout 1:20; or about 30:1 to about 1:15; or about 20:1 to about 1:10; orabout 15:1 to about 1:5; or about 10:1 to about 1:1; or any ranges inbetween such as1:20 to 20:1,or preferably from 1:10 to 10:1

Propellant

The composition requires the addition of a propellant in order togenerate a foam.

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof In one or more embodiments ahydrocarbon mixture AP-70 is used. In one or more other embodiments alower pressure hydrocarbon mixture AP-46 is used. Both contain butane,propane, isobutene although in different proportions. AP-46 is composedof about 16% w/w of propane, about 82% w/w of isobutane and about 2% w/wof propane. AP-70 is composed of about 50% w/w of propane, about 20% w/wof isobutane and about 30% w/w of propane. Hydrofluorocarbon (HFC)propellants are also suitable as propellants in the context disclosedherein. Exemplary HFC propellants include 1,1,1,2 tetrafluorethane(Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethylether is also useful. In one or more embodiments use of compressed gases(e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is alsopossible.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

Any concentration of the propellant, which affords an acceptable foam isuseful in accordance with the present invention. In certain embodimentsthe propellant makes up between about 3% and about 25% by weight of thefoamable composition, or between about 20% by weight and about 30%, orbetween about 20% by weight and about 35% by weight and preferablybetween about 5% by weight and about 16% by weight of the composition.In preparing the formulations the ingredients other than propellant arecombined to 100% and the propellant is added thereafter so that theratio of formulation to propellant can range from 100:3 to 100:35, 100:3to 100:30, 100:3 to 100:25 or preferably 100:5 to 100:16.

In one or more embodiments the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofpropellant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise. In one or more embodiments such system is used toexpel foam into a body cavity where the amount of propellant releasedinto the cavity is minimized.

Without being bound to any theory, it can be supposed that in certainembodiments in the absence of an independent oil phase, hydrocarbonpropellant is partially solubilized by the SCA and the fatty alcoholsand or fatty acids present in the composition, thus providing a clearcomposition. It was noted from a visual impaction that the fatty acidsand alcohols were dissolved in the composition.

Suspensions

In one or more embodiments the active or cosmetic ingredient iscompletely soluble in the formulation or a phase thereof In certainother embodiments it is provided as a suspension. For example, benzylperoxide (‘BPO’) or microsponges comprising an active ingredient such asretinoic acid or other encapsulated bodies, such as described herein.The following description applied to BPO will also apply with thenecessary changes to other solid agents, microspheres and other bodies.As can be appreciated, forming a homogeneous suspension of a BPO orother solid particle or body in foamable formulation using a formulationwith high viscosity—so that even after addition of propellant theformulation has a high viscosity—in order to try and stabilize the oildroplets and BPO particles, minimize particle motion and discouragegravitational sedimentation in the canister in which the formulation isstored simply will not do for foamable compositions. Such viscousformulations are not desirable for foamable compositions since they havelow flowability and may exhibit one or more of the following: are notshakable; form a block, i.e., a solid with no flowable mass, in thecanister; do not result in uniform expulsion; and if expulsed may beaccompanied by unwanted phenomena such as one or more of jets, tailingand noise.

Unexpectedly it has been discovered that it is possible to makecompositions which are truly flowable and have low viscosity in whichthe propellant forms part of the oil phase of the emulsion formulationbut nevertheless surprisingly does not make the formulationsubstantially vulnerable to phase separation and or sedimentation.Moreover these compositions are stable and are able to form breakablefoam of quality that spreads easily and is able to deliver an effectiveand measurable amount of active agent homogeneously to a target surface.

One key element is the polymeric agent used in the formulation. Thepolymeric agent can contribute to the stability and stabilization of theformulation. Concentrations of polymeric agents and other thickenershave in the past been used to achieve very high viscosities of at least20,000 centipoises (cps) to a million or more cps. Surprisingly by usinga polymer in concentrations and conditions, which results in lowerviscosities, for example, of the order of about 7000 to about 8000 cpsor less for the pre-foam formulation whose viscosity is further reducedupon inclusion of propellant, it is possible to achieve, for example, astable BPO formulation that produces breakable (non thermolabile) foamof good quality even after addition of propellant and even though thefoamable formulation with propellant is fluid and easily shakable. In apreferred embodiment the viscosity of a formulation comprisingpropellant is below about 5000 cps and in a more preferred embodiment itis below about 3000 cps. At such low levels of viscosity, one wouldexpect a suspended solid active agent such as BPO to precipitate out ofsolution. In the low viscosity formulations provided herein, BPO shouldremain homogeneously dispersed in suspension. For pharmaceuticalapplications, BPO needs to be homogeneous to ensure that the amount ofBPO in the first dose and the last dose is sufficiently uniform. Withoutbeing bound to any theory it is anticipateded that in order to form ahomogenous suspension of BPO a carbomer would be included at a pH whichat which its expansion is reduced.

An important factor in the use of a polymeric agent is to ensure thepolymer(s) is appropriately and correctly swelled in the presence ofwater by adding an effective amount of base. Without being bound by anytheory it may be the case that the lower levels of polymeric agent stillform a semi water gel like infrastructure that unexpectedly is able tostabilize the BPO physically and chemically at low viscosities.

In an embodiment the polymer is an amphiphilic polymer, such as, anacrylates/C10-30 alkyl acrylate crosspolymer. The hydrophilic andhydrophobic regions of these polymers serve to interact with andstabilize hydrophilic and lipophilic components, respectively, of acomposition. In one embodiment the polymeric agent is a carbomer.

By way of example, suitable amphiphilic polymers include cross linkedcopolymers of acrylic acid and a hydrophobic comonomer, such as PemulenTR-1 and Pemulen TR-2 (Acrylates/C10-30 alkyl acrylate crosspolymer),ETD 2020 and Carbopol 1382 (all, Acrylates/C10-30 alkyl acrylatecrosspolymer), Natrosol CS Plus 330 and 430 and Polysurf 67 (all, cetylhydroxyethyl cellulose), Aculyn 22 (acrylates/steareth-20 methacrylatecopolymer), Aculyn 25 (acrylates/laureth-25 methacrylate copolymer),Aculyn 28 (acrylates/beheneth-25 methacrylate copolymer), Aculyn 46(PEG-150/stearyl alcohol/SMDI copolymer), Stabylen 30 (acrylates/vinylisodecanoate), Structure 2001 (acrylates/steareth-20 itaconatecopolymer), Structure 3001 (acrylates/ceteth-20 itaconate copolymer) andStructure Plus (acrylates/aminoacrylates/C10-30 alkyl PEG 20 itaconatecopolymer), where PEG is polyethylene glycol, PPG is polypropyleneglycol.

Other exemplary amphiphilic copolymers include silicone polymers such asamphiphilic silicone polyols or copolyol, for example cetyl dimethiconcopolyol and dimethicone copolyol PPG-3 oleyl ether, acetylated starchderivatives, amphiphilic modified starches, and amphiphilic blockcopolymers of ethylene oxide, propylene oxide and/or propylene glycol(also known as “poloxamer”).

The gelling agent may include other types of gelling agents, incombination with an amphiphilic copolymer. A non limiting list of othertypes such as water soluble cellulose, or gums like guar and xantham isprovided below.

A further element and aid to reducing viscosity in the presence ofgelling agents is the use of a buffer or buffer complex, such as citratebuffer or alternatively lactate to cause a thick emulsion gel or pastecontaining carbomer to become fluid. Other similar buffers may work. Nonlimiting examples of appropriate possible buffers, which may achieve thesame objective are acetate, malate, sorbate, succinate and tartrate.

Optional Ingredients

Optionally, the foamable composition further includes at least oneorganic carrier selected from the group consisting of a polar solvent, ahydrophobic organic carrier and mixtures thereof, at a concentration ofabout 2% to about 50% by weight.

Hydrophilic Solvent

A hydrophilic solvent is a solvent that is more miscible with water thanwith a hydrophobic compound.

Examples of suitable hydrophilic solvents are water, propylene glycol,low molecular weight polyethylene glycols, methoxyisopropanol, PPG-2propyl ether, PPG-2 butyl ether, PPG-2 methyl ether, PPG-3 methyl ether,dipropylene glycol propyl ether, dipropylene glycol butyl ether,dipropylene glycol, methyl propanediol, propylene carbonate, watersoluble/dispersible polypropylene glycols, ethoxylated polypropyleneglycol, glycerin, sorbitol, hydrogenated starch hydrolysate, siliconeglycols, and their mixtures and the like. In one or more embodimentswater is a hydrophilic solvent.

In one or more embodiments, the composition comprises a hydrophilicsolvent.

In one or more embodiments, the short chain alcohol is replaced by is ahydrophilic solvent.

In one or more embodiments, the hydrophilic solvent is a polyol. Apolyol is an organic substance that contains at least two hydroxy groupsin its molecular structure. In one or more embodiments, the foamablecarrier contains at least one diol In one or more embodiments, thefoamable carrier contains at least one triol. In one or moreembodiments, the polyol is a mixture of polyols. In one or moreembodiments, the mixture of polyols contains at least one diol and atleast one triol. In one or more embodiments the hydrophilic solvent is apolar solvent.

In one or more embodiments, the hydrophilic solvent is selected from thegroup consisting of propylene glycol, low molecular weight polyethyleneglycols and glycerin.

Polar Solvent

A “polar solvent” is an organic solvent which is typically soluble inboth water and oil.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure.

In one or more embodiments, the polar solvent contains a diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butanediol (e.g., 1,4-butaneediol), butanediol (e.g.,1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Additional examples of polar solvents include polyols, such as glycerol(glycerin), propylene glycol, hexylene glycol, diethylene glycol,propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol,other glycols, alkanols, such as dialkylamino acetates, and admixturesthereof, dimethyl isosorbide, ethyl proxitol, dimethylacetamide (DMAc)and alpha hydroxy acids, such as lactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof

Yet, in additional embodiments, the polar solvent is an aprotic polarsolvent, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF),acetonitrile, acetone, methyl ethyl ketone, 1,4-Dioxane andtetrahydrofuran (THF). Additional non-limiting examples includeN-methylpyrrolidone, pyridine, piperidine, dimethyl ether,hexamethylphosphorotriamide, dimethylformanide, methyl dodecylsulfoxide, N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone) andazone (1-dodecylazacycloheptan-2-one).

Many polar solvents, for example propylene glycol, glycerin, DMSO andazone possess the beneficial property of a dermal, transdermal ortrans-mucosal drug delivery enhancer.

In one or more embodiments, the polar solvent is a dermal, transdermalor trans-mucosal drug delivery enhancer.

Many polar solvents, for example propylene glycol and glycerin, possessthe beneficial property of a humectants.

In one or more embodiments, the polar solvent is a humectant.

Hydrophobic Solvent/Emollient

One or more hydrophobic solvents are optionally included in thecomposition, in order to add to the sensory properties of thecomposition and/or in order to impart skin conditioning properties. Inan embodiment, the hydrophobic solvent is an emollient, i.e., asubstance that softens and soothes the skin. Emollients are used tocorrect dryness and scaling of the skin. The hydrophobic solvent and/orthe emollient can be selected from the group consisting of mineral oil,alkyl esters of fatty acids such as isopropyl palmitate, isopropylisostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate,cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolinalcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryllinoleate, wheat germ glycerides, arachidyl propionate, myristyllactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, triisocetylcitrate, octyl dodecanol, maleated soybean oil, unsaturated orpolyunsaturated oils, such as olive oil, corn oil, soybean oil, canolaoil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seedoil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil,salmon oil, flaxseed oil, wheat germ oil, evening primrose oils;essential oils; and silicone oils, such as dimethicone, cyclomethicone,polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, apolyether siloxane copolymer and apoly(dimethylsiloxane)-(diphenyl-siloxane) copolymer. In certainembodiments the carrier can comprise a petrolatum where it is providedin modest or minor amounts of up to about 5%.

In one or more preferred embodiments the hydrophobic solvent has atleast a degree of solubility in the SCA present in the formulation.

In order to improve the miscibility or the dispersion of a hydrophobicsolvent in the formulation, fatty alcohols and preferably fatty acidscan be added in order to form an emulsion which is either stable oreasily re-dispersible by shaking. In certain embodiments effectiveamounts of polymeric agents may be added. By re-dispersible on shakingis meant that the formulation on reasonable moderate shaking of about afew times will provide a uniform emulsion which will remain relativelystable for at least a reasonable short period of time sufficient toallow it to be dispensed from the pressurized canister. In one or moreembodiments a combination of one or more fatty acids with one or morefatty alcohols is used to help provide an emulsion which has at least ashort term stability and is easily re-dispersible on shaking.

Modulating Agent

In one or more embodiments the formulation includes a modulating agent.The term modulating agent is used to describe an agent which can improvethe stability of or stabilize a foamable carrier or composition and oran active agent by modulating the effect of a substance or residuepresent in the carrier or composition.

In one or more embodiments the substance or residue may for example beacidic, basic or a buffer agent, which can affect pH in a composition.The agent can be any of the known buffering systems used inpharmaceutical or cosmetic formulations as would be appreciated by a manof the art. It can also be an organic acid, a carboxylic acid, a fattyacid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid anorganic base or a nitrogen containing compound. In certain embodimentsthe modulating agent is a buffer, as defined by Van Slyke [Van Slyke, J.Biol. Chem. 52, 525 (1922)], as “a substance which by its presence insolution increases the amount of acid or alkali that must be added tocause unit change in pH.”

Certain active agents are known to be stable at a narrow pH range. Forexample, corticosteroids are typically stable at acidic pH levels, whilevitamin D3 derivatives are stable at basic pH. Hence, in certainembodiments the modulating agent is selected to exert a pH modifyingeffect, which results in the desirable pH level.

In certain embodiments, the pH modifying agent is selected from thegroup including citric acid and sodium citrate.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since better protection against vaginal infection is attained with pHlower than about 4.5.

In an embodiment, the modulating agent is an antioxidant or a radicalscavenger. Non-limiting examples of antioxidants/radical scavengers areascorbic acid and derivatives, tocopherol or derivatives thereof(succinate, or sorbate or acetate or other esters), propyl galate,butylated hydroxy toluene and butyl hydroxy anisol. Non-limitingexamples of positive ionization agents are benzyl conium chloride, andcetyl pyridium chloride. Non-limiting examples of negative ionizationagents are sodium lauryl sulfate, sodium lauryl lactylate andphospholipids.

In one or more further embodiments the modulating agent is a chelatingor sequestering or complexing agent that is sufficiently soluble orfunctional in the solvent to enable it to “mop up” or “lock” metal ions.In one or more embodiments a preferred non limiting example is EDTA.

Modulating agents may be added to the compositions of the subjectinvention, as necessary to provide their function of improving thestability of or stabilize a foamable carrier or composition and or anactive agent. The modulating agent concentration can preferably rangefrom about 0.1% to about 10%, more preferably from about 1% to about 5%,of the composition. In certain cases the active agent itself is themodulating agent, alone or in combination with another modulating agent,and in such cases it will be added at an effective dose which may beoutside these ranges. For example azelaic acid may be at about 15% ofthe composition.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti perspirants, anti-static agents, bulking agents,cleansers, colorants, skin conditioners, deodorants, diluents, dyes,fragrances, hair conditioners, herbal extracts, humectants, keratolyticagents, pearlescent aids, perfuming agents, pH preservatives,protectants, skin penetration or permeation enhancers, softeners,solubilizers, sunscreens, sun blocking agents, sunless tanning agents,viscosity modifiers, flavanoids and vitamins. As is known to one skilledin the art, in some instances a specific additional component may havemore than one activity, function or effect.

In one or more further embodiments the composition further includesabout 0.1% to about 5% of a humectant. In one or more furtherembodiments the humectant is selected from the group consisting of PEG400, propylene glycol and glycerin or mixtures of two or more thereof

Substantially Surfactant Free

According to one or more embodiments, the foamable composition issubstantially surfactant-free. In the context herein, the term“substantially surfactant free composition” relates to a compositionthat contains a total of less than about 0.4% of a surfactant selectedfrom the group consisting of non-ionic, anionic, cationic, zwitterionic,amphoteric and ampholytic surfactants. Preferably, the compositioncomprises less than about 0.2% by weight of a surfactant and morepreferably less than about 0.1%. Non-surfactant compositions willcomprise no or negligible levels of surface active agents (essentiallysurfactant free).

In the art, the term surface active agent or surfactant is sometimesused loosely and some publications may refer to compounds that have asupportive role, such as co-surfactants as surfactants. Substances whichcannot function as true surfactants on their own but only in the contextof being used with another surfactant are not considered to besurfactants for the purposes described herein. Thus, in the contextherein, a fatty alcohol is not regarded a surfactant, and likewise, afatty acid is not regarded as a surfactant In contrast, however, anether or an ester formed from them can be a surfactant. Also quaternaryammonium compounds and ions, which for example are not infrequently seenin hair preparations, are not regarded as surfactants.

Physical Characteristics of the Foamable Composition and Foam

A foamable composition manufactured according to one or more embodimentsherein is very easy to use. When applied onto the afflicted body surfaceof mammals, i.e., humans or animals, it is in a foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition is a single phasesolution. In certain circumstances, the active agent is insoluble and ispresented as a homogenous suspension and the formulation is turbid orcloudy. In one or more other embodiments the formulation prior toaddition of propellant is an emulsion. In one or more embodiments thefoam composition has an acceptable shelf-life of at least one year, orat least two years at ambient temperature. A feature of a product forcosmetic or medical use is long term stability. Propellants, which are amixture of low molecular weight hydrocarbons, tend to impair thestability. The foamable compositions herein are surprisingly stable,even in the absence of customary surfactants.

Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing a substantial amount ofsemi-solid hydrophobic solvents, e.g., white petrolatum, as the mainingredients of the oil phase of the emulsion, will likely exhibit highviscosity and poor flowability and are inappropriate candidates for afoamable composition.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof a more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.20 g/mL or less than 0.12 g/mL, depending ontheir composition and on the propellant concentration.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests. In one or more certain limitedembodiments the formulation is poorly shakable but is neverthelessflowable.

Breakability/Collapse Time

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on one hand the foam should preferably not be “quickbreaking”, i.e., it should be stable upon release from the pressurizedcontainer and not break as a result of exposure to skin temperature; andon the other hand, it should be “breakable”, i.e., it should spreadeasily, break down and absorb into the skin or membrane upon applicationof mild shear force. The breakable foam is thermally stable, yet breaksunder shear force. Shear-force breakability of the foam is clearlyadvantageous over thermally-induced breakability. Thermally sensitivefoams start to collapse immediately upon exposure to skin temperatureand, therefore, cannot be applied on the hand and afterwards deliveredto the afflicted area.

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least stable in the shortterm so as to allow a user sufficient time to comfortably handle andapply the foam to a target area without being rushed and or concernedthat it may rapidly collapse, liquefy and or disappear. Collapse time,as an indicator of thermal sensitivity, is examined by dispensing agiven quantity of foam and photographing sequentially its appearancewith time during incubation at 36° C.

Short chain alcohols are known to cause foam to be thermolabile and“quick breaking.” However, in certain embodiments herein, despite thepresence of high alcohol content, quite unexpectedly the foam issubstantially thermally stable. By “substantially thermally stable” itis meant that the foam upon application onto a warm skin or body surfaceat about 35-37° C. does not collapse within about 30 seconds. Thus, inone or more embodiments the simple collapse time of the foam is morethan about 30 seconds or more than about one minute or more than abouttwo minutes. In one or more limited embodiments simple collapse time canbe a little shorter than 30 seconds, but not less than about 20 seconds.In one or further or alternative embodiments the collapse time ismeasured by introducing a sample of foam into an incubator at 36° C. andthe collapse time of the foam is more than 30 seconds or more than aboutone minute or more than about two minutes.

Pharmaceutical Composition

The foamable composition is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. In one or moreembodiments the active agent is soluble in the composition of a phasethereof. In one or more other embodiments it is insoluble. Wheninsoluble the active agent is presented as a suspension or on a carrierwhich can include microspheres and the like.

Suitable active agents include but are not limited to an active herbalextract, an acaricides, an age spot and keratose removing agent, anallergen, an alpha hydroxyl acid, an analgesic agent, an antiacne agent,an antiallergic agent, an antiaging agent, an antibacterial agent, anantibiotic, an antiburn agent, an anticancer agent, an antidandruffagent, an antidepressant, an antidermatitis agent, an antiedemic anent,an antifungal agent, an antihistamine, an antihelminth agent, anantihyperkeratolyte agent, an anti-infective agent, an antiinflammatoryagent, an antiirritant, an antilipemic agent, an antimicrobial agent, anantimycotic agent, an antioxidant, an antiparasitic agent, anantiproliferative agent, an antipruritic agent, an antipsoriatic agent,an antirosacea agent, an antiseborrheic agent, an antiseptic agent, anantiswelling agent, an antiviral agent, an anti-wart agent, ananti-wrinkle agent, an antiyeast agents, an astringent, a beta-hydroxyacid, benzoyl peroxide, a topical cardiovascular agent, achemotherapeutic agent, a corticosteroid, an immunogenic substance, adicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator,a haptene, a hormone, a hydroxy acid, an immunosuppressant, animmunoregulating agent, an immunomodulator, an insecticide, an insectrepellent, a keratolytic agent, a lactam, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, a mitocide,a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizingagent, a pediculicide, a peptide, a protein, a photodynamic therapyagent, a radical scavenger, a refatting agent, a retinoid, a sanative, ascabicide, a self tanning agent, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a vasoconstrictor, avasodilator, a vitamin, a vitamin A, a vitamin A derivative, a vitaminB, a vitamin B derivative, a vitamin C, a vitamin C derivative, avitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F, avitamin F derivative, a vitamin K, a vitamin K derivative, a woundhealing agent and a wart remover. As is known to one skilled in the art,in some instances a specific active agent may have more than oneactivity, function or effect.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration profile; and (4) mitigationof adverse effects, due to the controlled release of the active agentfrom the encapsulation particles.

Solubility of an Active Agent

In an embodiment, the active agent is not fully soluble in water or, isnot fully soluble in the SCA, is not fully soluble in the presence of ahydrophobic solvent in the formulation, or is not fully soluble in theoil phase of the emulsion. In one or more embodiments the active agentis soluble in the composition or a phase thereof In an embodiment, theaprotic polar solvent is present in the composition in an amountsufficient to solubilize the active agent in the composition. In one ormore embodiments, aprotic polar solvent acts to improve the solubilityof an active agent. In certain preferred embodiments, the active agentto be solubilized is selected from the group consisting of anon-steroidal anti-inflammatory agent, a local anesthetic agent, asteroid, an immunomodulator, a keratolytically active agent, ananti-acne agent, an anti-rosacea agent, an antiinfective agent and ananti-psoriasis agent. In a preferred embodiment the active agent to besolubilized is diclofenac.

Exemplary Groups of Active Agents Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone valerate and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

In certain embodiments, the steroid is a hormone or a vitamin, asexemplified by pregnane, cholestane, ergostane, aldosterone,androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, glucocorticoid, lanosterol, mometasonefuroate, prednisolone, prednisone, progesterone, spironolactone,timobesone and testosterone, as well as analogs, derivatives, salts,ions and complexes thereof.

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the steroid.

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent (also termedherein “NSAID”) is a pharmaceutically active compound, other than acorticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole—aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof Exemplary arylpropionic acid derivative include,in a non limiting fashion, are ibuprofen, naproxen, flubiprofen,ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 Inhibitors include, in an exemplary mannerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonanilides (e.g., Nimesulide) and salts and derivatives thereof

In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the NSAID, asexemplified herein by the solubilization of diclofenac.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope, the anesthetic agent can be selected from the groupconsisting of benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceuticallyacceptable salts thereof and mixtures of such anesthetic agents. Anymixture of synergistically beneficial anesthetic agents is contemplated.In an embodiment, the aprotic polar solvent is present in thecomposition in an amount sufficient to solubilize the anesthetic agent.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of a foamablecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the treatment ofdermatological disorders that involve dry skin, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxybenzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene)having anti-pigmentation properties, hydroquinone is also known to bekeratolytic. These compounds also exhibit antiseptic properties. Cresolsalso possess bactericidal and keratolytic properties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal, as well asadapalene, tazarotene, isotretinoin, acitretin and additional retinoidsknown in the art of pharmaceuticals and cosmetics are another class ofkeratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulatorImmunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune systemImmunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus,laquinimod and imiquimod, as well as analogs, derivatives, salts, ionsand complexes thereof Such compounds, delivered in the foam, areespecially advantageous in skin disorders such as psoriasis, eczema andatopic dermatitis, where the large skin areas are to be treated. In anembodiment, the aprotic polar solvent is present in the composition inan amount sufficient to solubilize the immunomodulator.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as anyadditional retinoids known in the art of pharmaceuticals and cosmetics;and analogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such aserythromycin and clyndamycin, coal tar, zinc salts and complexes, andcombinations thereof, in a therapeutically effective concentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agents can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, vitamin D and derivatives and analogsthereof, including vitamin D3 analogs such as calcitriol, calcipotriol;retinoids, and photodymamic therapy agents.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

The Foamable Composition Essential Ingredients as Active Agents

In certain embodiments, the short chain alcohol possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent.” For example, ethanol kills microorganisms and can be effectivein the treatment or prevention of conditions that involve microbialinfection, such as bacterial, fungal and viral conditions. Additionally,the defatting effect of alcohol is useful for the treatment ofconditions which involve oily skin, such as acne, Rosacea and seborrheicdermatitis. The combination of a short chain alcohol and atherapeutically effective fatty alcohol or fatty acid may afford asynergistic beneficial effect in conditions characterized, for example,by infection and/or inflammation.

Because short chain alcohols are known to increase the rate ofabsorption of some compounds through organic tissues including skin andnails, formulations comprising such alcohols can be used as a drugdelivery system.

Combination of Active Agents

Several disorders involve a combination of more than one etiologicalfactor; and therefore, the use of more that one active agents isadvantageous. For example, psoriasis involves excessive cellproliferation and inadequate cell differentiation as well asinflammation. Atopic dermatitis involves keratinocyte growthabnormality, skin dryness and inflammation. Bacterial, fungal and viralinfections involve pathogen colonization at the affected site andinflammation. Hence, in many cases, the inclusion of a combination ofactive agents in the foamable pharmaceutical composition can bedesirable. Thus, in one or more embodiments, the foamable compositionfurther includes at least two active agents, in a therapeuticallyeffective concentration.

Fields of Applications

The foamable composition is suitable for treating any inflicted surface.In one or more embodiments, foamable carrier is suitable foradministration to the skin, a body surface, a mucosal surface and a bodycavity, e.g., the cavity and/or the mucosa of the nose, mouth and eye,the ear, the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”).

By selecting a suitable active agent, or a combination of two or moreactive agents, the foamable composition is useful in treating an animalor a human patient having any one of a variety of dermatologicaldisorders, including dermatological pain, dermatological inflammation,acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acnefulminans, nodular papulopustular acne, acne conglobata, dermatitis,bacterial skin infections, fungal skin infections, viral skininfections, parasitic skin infections, skin neoplasia, skin neoplasms,pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas,cutaneous abscesses, necrotizing subcutaneous infections, scalded skinsyndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing moistens, gangrene, scarring, and vitiligo.

Likewise, the foamable composition is suitable for treating a disorderof a body cavity or mucosal surface, e.g., the mucosa of the nose,mouth, eye, ear, respiratory system, vagina or rectum. Non limitingexamples of such conditions include chlamydia infection, gonorrheainfection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV),genital warts, bacterial vaginosis, candidiasis, chancroid, granulomaInguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC),molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis,vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvardystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis,pelvic inflammation, endometritis, salpingitis, oophoritis, genitalcancer, cancer of the cervix, cancer of the vulva, cancer of the vagina,vaginal dryness, dyspareunia, anal and rectal disease, analabscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease,hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation,polyps of the colon and rectum.

In an embodiment the composition is useful for the treatment of aninfection. In one or more embodiments, the composition is suitable forthe treatment of an infection, selected from the group of a bacterialinfection, a fungal infection, a yeast infection, a viral infection anda parasitic infection.

In an embodiment the composition is useful for the treatment of a wound,ulcer and burn.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.

The composition is also suitable for administering a hormone to the skinor to a mucosal membrane or to a body cavity, in order to deliver thehormone into the tissue of the target organ, in any disorder thatresponds to treatment with a hormone.

In an embodiment the target site is selected from the group consistingof the skin, a body cavity, a mucosal surface, the nose, the mouth, theeye, the ear canal, the respiratory system, the vagina and the rectum.

In an embodiment the disorder is selected from the group consisting ofdermatological pain, dermatological inflammation, acne, acne vulgaris,inflammatory acne, non-inflammatory acne, acne fulminans, nodularpapulopustular acne, acne conglobata, dermatitis, bacterial skininfections, fungal skin infections, viral skin infections, parasiticskin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,necrotizing subcutaneous infections, scalded skin syndrome,folliculitis, furuncles, hidradenitis suppurativa, carbuncles,paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeastskin infections, warts, molluscum contagiosum, trauma or injury to theskin, post-operative or post-surgical skin conditions, scabies,pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea,lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme,erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn,photosensitivity, pemphigus, bullous pemphigoid, dermatitisherpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skinulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, poison ivy, poison oak, contact dermatitis, atopicdermatitis, rosacea, purpura, moniliasis, candidiasis, baldness,alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermaldysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hairloss, Hailey-Hailey disease, chemical or thermal skin burns,scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis,necrotizing myositis, gangrene, scarring, and vitiligo, chlamydiainfection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, humanpapillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis,chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulentcervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum; and whereinthe active agent is suitable for treating said disorder.

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand ostheoarthritis; the active agent is a nonsteroidalanti-inflammatory drug, given at a therapeutically effectiveconcentration.

In one or more embodiments, the active agent may be a placebo or acosmetic agent.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin. Alternatively it maybe used with cosmetic effect for example as a cosmetic remover. It canbe dispensed in small quantities as a foam targeted to a surface andapplied locally with mechanical force causing the foam to break.

Examples

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the foamablecompositions and methods described herein. The examples are for thepurposes of illustration only and are not intended to be limiting. Manyvariations will suggest themselves and are within the full intendedscope.

Example 1 General Manufacturing Procedures

The following procedures are used to produce the foam samples describedin the examples below, in which only the steps relevant to eachformulation are performed depending on the type and nature ofingredients used.

Step 1: Ethanol and, if present, humectants are mixed at roomtemperature. Polymers or gelling agents, if present, are added at roomtemperature under mixing until formulation homogeneity is obtained.Surfactants and fatty alcohols or fatty acids, if present, are addedunder agitation until complete dissolution.

Step 2: Any pH-buffering agents are added to water at room temperatureunder mixing until complete dissolution.

Step 3: The alcoholic phase is added to the water phase under mixinguntil homogeneity is obtained.

Step 4: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing. Optionally a metered dosage unitcan be utilized to achieve delivery of repeatable measured doses offoam, f. or example as described in U.S. Provisional Application No.61/363,577 entitled “APPARATUS AND METHOD FOR RELEASING A UNIT DOSE OFCONTENT FROM A CONTAINER,” filed Jul. 12, 2010, which is incorporatedherein by reference.

Note: hydrophobic substances, if present, are added to the alcohol phasewith the fatty alcohols and or fatty alcohols.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production offoamable compositions disclosed herein. Equivalent materials from othermanufacturers can also be used satisfactorily. Chemical Name FunctionCommercial Name Supplier Acrylates/C10-30 alkyl Gelling agent PemulenTR2 Noveon acrylate crosspolymer Behenyl alcohol Foam adjuvant Lanette22 Cognis Benzoyl Peroxide Active agent Benzoyl Peroxide SpectrumBetamethasone Valerate Active agent Betamethasone Crystal ValeratePharma Carbomer 934P Gelling agent Carbopol 934P Spectrum Cetostearylalcohol Foam adjuvant Speziol C16-C18 Cognis Cetyl alcohol Foam adjuvantSpeziol C16 Cognis Citric acid pH modifying agent Citric acid R. de HaenClindamycin Phosphate Active agent Clindamycin Uqifa PhosphateCoco-betaine Surfactant Dehyton Cognis Diclofenac sodium Active agentDiclofenac sodium Sriken Ethanol absolute Solvent Ethanol Bio LabGlycerin Humectant Glycerin Cognis Hexylene Glycol Solvent HexyleneGlycol Spectrum Hydroxypropyl cellulose Gelling agent Klucel EF HerculesHydroxypropyl Gelling agent Methocel K100M Colorcon methylcellulose DowLaureth-23 Surfactant Brij 35P Uniqema Mometasone Furoate Active agentMometasone Sicor Furoate Myristic acid Foam adjuvant Myristic acidSpectrum Myristyl alcohol Foam adjuvant Speziol C14 Cognis Oleth-20Surfactant Samulsol 98 Seppic PEG-40 Stearate Surfactant Myrj 52S CrodaPoloxamer 407 Gelling agent Lutrol F127 BASF Polyethylene glycol 400Humectant PEG-400 Inoes Polysorbate 60 Surfactant Polysorbate 60 CognisPropane/Isobutane/Butane Propellant AP-70 Aeropress (55:18:27)Corporation Propylene glycol Humectant Propylene Glycol Gadot Sodiumcitrate pH modifying Sodium Citrate Archer agent Daniels Mild Sodiumlauryl sarcosinate Surfactant Lanette E PH Cognis Sodium Lauryl SulfateSurfactant Sodium dodecyl Cognis sulfate Stearic acid Foam adjuvantStearic acid Spectrum Stearyl Alcohol Foam adjuvant Speziol C18 CognisTriethanolamine pH modifying TEA Gadot agent Xanthan Gum Gelling agentXanthan Gum 11K CP Kelco USProduction under Vacuum

Optionally, the foamable carrier may be produced under nitrogen andunder vacuum. Whilst the whole process can be carried out under anoxygen free environment, it can be sufficient to apply a vacuum afterheating and mixing all the ingredients to obtain an emulsion orhomogenous liquid. Preferably the production chamber is equipped toapply a vacuum.

Canisters Filling and Crimping

Each aerosol canister is filled with the pre-foam formulation (“PFF”,i.e., foamable carrier) and crimped with valve using vacuum crimpingmachine. The process of applying a vacuum will cause most of the oxygenpresent to be eliminated. Addition of hydrocarbon propellant may withoutbeing bound by any theory further help to reduce the likelihood of anyremaining oxygen reacting with the active ingredient. It may do so,without being bound by any theory, by one or more of dissolving in, tothe extent present, the oil or hydrophobic phase of the formulation, bydissolving to a very limited extent in the aqueous phase, by competingwith some oxygen from the formulation, by diluting out any oxygen, by atendency of oxygen to occupy the dead space, and/or by oxygen occupyingpart of the space created by the vacuum being the unfilled volume of thecanister or that remaining oxygen is rendered substantially ineffectivein the formulation.

Pressurizing & Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

Tests

By way of non-limiting example the objectives of hardness, collapse timeand freeze-thaw cycle (“FTC”) stability tests are briefly set out belowas would be appreciated by a person of the art.

Collapse Time

Collapse Time, which is the measure of thermal stability, is examined bydispensing a given quantity of foam and photographing sequentially itsappearance with time during incubation at 36° C. The collapse timeresult is defined as the time when the foam height reaches 50% of itsinitial height or if the foam has not yet reached 50% of its initialheight after say 180 seconds then the collapse time is recorded asbeing >180. By way of illustration one foam may remain at 100% of itsinitial height for three minutes, a second foam may reach 90% of itsinitial height after three minutes, a third foam may reach 70% of itsinitial height after three minutes, and a fourth foam may reach 51% ofits initial height after three minutes, nevertheless in each of thesefour cases the collapse time is recorded as >180secs since for practicalpurposes for easy application by a patient to a target the majority ofthe foam remains intact for more than 180secs. If the foam for examplereaches 50% of its original height after say 100 seconds it would berecorded as having a collapse time of 100 seconds. It is useful forevaluating foam products, which maintain structural stability at skintemperature for at least 1 minute. Foams which are structurally stableon the skin for at least one minute are termed “short term stable”carriers or foams.

Alternatively, a Simple Collapse Time can be assessed by placing a foamsample on the warm fingers of a volunteer and measuring the time ittakes to melt on the fingers, for example, as observed in Example 4herein.

Density

In this procedure, the foam product is dispensed into vessels (includingdishes or tubes) of a known volume and weight. Replicate measurements ofthe mass of foam filling the vessels are made and the density iscalculated. The canister and contents are allowed to reach roomtemperature. The canister is shaken to mix the contents and then 5-10 mLof the contents is dispensed and discarded. Next the foam is dispensedinto a pre-weighed tube, filling it until excess is extruded.Immediately excess foam is leveled off and removed at both ends and thefilled tube is weighed on the weighing balance.

Viscosity

Viscosity is measured with Brookfield LVDV-II +PRO with spindle SC4-25at ambient temperature and 10, 5 and 1 RPM. Viscosity is usuallymeasured at 10RPM. However, at about the apparent upper limit for thespindle of ˜>50,000CP, the viscosity at 1RPM may be measured, althoughthe figures are of a higher magnitude. Unless otherwise stated viscosityof the pre-foam formulation (PFF) is provided. It is not practical totry and measure the viscosity of the foamable formulation with regularpropellants since they have to be stored in sealed pressurized canistersor bottles. In order to simulate the viscosity in the foamableformulations with propellant an equivalent weight of pentane (a lowvolatile hydrocarbon) is added to and mixed with the pre-foamformulation and left overnight. The viscosity is then measured as above.

FTC (Freeze Thaw Cycles)

Foam appearance under extreme conditions of repeated heating and coolingis evaluated by cycling through cooling, heating, (first cycle) cooling,heating (second cycle) etc., conditions, commencing with −10° C. (24hours) followed by +40° C. (24 hours) and measuring the appearancefollowing each cycle. The cycle is repeated for up to three times.

Chemical Stability

The amount of active agent present is analyzed in foam expelled fromvarious pressurized canisters containing foam formulations using HPLC.Analysis is carried out at zero time and at appropriate time intervalsthereafter. The canisters are stored in controlled temperatureincubators at one or more of 5° C., at 25° C., at, 40° C. and at 50° C.At appropriate time intervals canisters are removed and the amount ofactive agent in the foam sample is measured.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital cameraequipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used is a Nikon D4OX Camera(resolution 10MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DG HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Microscope Size:

The light microscope enables observing and measuring particles from fewmillimeters down to one micron. Light microscope is limited by thevisible light wavelength and therefore is useful to measuring size ofparticles above 800 nanometers and practically from 1 micron (1,000nanometers).

Shakability

Shakability represents the degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Shakability Scoring:

Good shakability (conforms to required quality specification) 2 Moderateshakability (conforms to required quality specification) 1 Not shakable(fails to meet required quality specification) but may 0 still beflowable and allow foam formation of quality Is substantially not ableto pass through valve Block

Example 2 Hydro-Alcoholic Formulations Containing a Combination ofSurfactants and Polymers

Several surfactants were used in combination with gelling agents(polymers) and checked for their foaming properties.

As described in Table 2a below, formulations 1, 7, 8 and 12 containinglaureth-23 or oleth-20 non-ionic surfactants in combination with variouspolymers did not give rise to foams but merely generated bubbly liquids.

TABLE 2a Formulations containing laureth-23 or oleth-20 Formulation 1 78 12 Ingredient % w/w % w/w % w/w % w/w Ethanol 51.00  51.50  50.50 51.00  Purified water 36.00  40.00  40.90  36.90  PEG 400 — — 5.00 5.00Propylene glycol 5.00 — — — Glycerin — 5.00 — — Hydroxypropyl — — 1.50 —cellulose Poloxamer 407 20% 5.00 — — 5.00 solution Carbomer 974 — 0.40 —— Triethanolamine — 0.10 — — Laureth-23 2.00 2.00 2.00 — Oleth-20 — — —2.00 Citric acid 0.40 0.40 0.07 0.07 Sodium citrate 0.60 0.60 0.03 0.03Total 100.00  100.00  100.00  100.00  Propellant AP-70 8.00 8.00 8.008.00 Results Foam Quality Poor Poor Poor Poor Product Clarity Yes No YesYes

As described in Table 2b below, formulations 2, 5 and 11 containingpolysorbate 60 and PEG 40 stearate non-ionic surfactants in combinationwith various polymers did not give rise to foams but merely generatedbubbly liquids.

TABLE 2b Formulations containing polysorbate 60 and PEG 40 stearateFormulation 2 5 11 Ingredient % w/w % w/w % w/w Ethanol 50.50  51.50 51.50  Purified water 40.00  40.00  40.90  PEG400 — — 5.00 Propyleneglycol — 5.00 — Glycerin 5.00 — — Hydroxypropyl 1.50 — — celluloseHydroxypropyl — 0.50 — methylcellulose Carbomer 974 — — 0.40Triethanolamine — — 0.10 Polysorbate 60 0.60 0.60 0.60 PEG 40 Stearate1.40 1.40 1.40 Citric acid 0.40 0.40 0.07 Sodium citrate 0.60 0.60 0.03Total 100.00  100.00  100.00  Propellant AP-70 8.00 8.00 8.00 ResultsFoam Quality Poor Poor Poor Product Clarity Yes Yes No

As described in Table 2c below, formulations 3, 9 and 10 containingsodium lauryl sulfate and coco-betaine (anionic and zwitterionicsurfactants) in combination with various polymers did not give rise tofoams but merely generated bubbly liquids.

TABLE 2c Formulations containing sodium lauryl sulfate and coco-betaineFormulation 3 9 10 % w/w % w/w % w/w Ingredient Ethanol 52.90 52.4051.90 Purified water 40.00 36.90 40.90 PEG 400 5.00 — — Propylene glycol— — 5.00 Glycerin — 5.00 — Hydroxypropyl cellulose — — 1.50 Poloxamer407 20% solution — 5.00 — Hydroxypropyl 0.50 — — methylcellulose Sodiumlauryl sulfate 0.30 0.30 0.30 Coco-betaine 0.30 0.30 0.30 Citric acid0.40 0.07 0.07 Sodium citrate 0.60 0.03 0.03 Total 100.00 100.00 100.00Propellant AP-70 8.00 8.00 8.00 Results Foam Quality Poor Poor PoorProduct Clarity Yes Yes Yes

As described in Table 2d below, formulations 17 and 18 containing sodiumlauryl sarcosinate and sodium cetearyl sulfate anionic surfactants incombination with various polymers did not give rise to foams but merelygenerated bubbly liquids.

TABLE 2d Formulations containing sodium lauryl sarcosinate and sodiumcetearyl sulfate Formulation 017 018 % w/w % w/w Ingredient Ethanol52.90 52.40 Purified water 40.90 36.90 PEG 400 5.00 — Glycerin — 5.00Poloxamer 407 20% solution — 5.00 Hydroxypropyl methylcellulose 0.50 —Sodium lauryl sarcosinate 0.30 0.30 Sodium cetearyl sulfate 0.30 0.30Citric acid 0.07 0.07 Sodium citrate 0.03 0.03 Total PFF components:100.00 100.00 Propellant AP-70* 8.00 8.00 Results Foam Quality Poor PoorProduct Clarity Yes Yes

As described in Table 2e below, formulations 52, 53 and 54 containingpolymeric agents alone such as Hydroxypropyl cellulose (acellulose-based polymer), poloxamer 188 (a polymer having somesurfactant-like properties) and Acrylates/C10-30 alkyl acrylatecrosspolymer (an amphiphilic polymer said to have some emulsifying-likeproperties) did not give foams but bubbly liquids.

TABLE 2e Formulations containing various polymeric agents Formulation 5253 54 % w/w % w/w % w/w Ingredient Ethanol 50.00 50.00 50.00 Purifiedwater 47.00 47.00 47.00 Hydroxypropyl cellulose 3.00 — 1.50 Poloxamer188 — 3.00 — Acrylates/C10-30 alkyl — — 3.00 acrylate crosspolymer Total100.00 100.00 100.00 Propellant AP-70 8.00 8.00 8.00 Results FoamQuality Poor Poor Poor

This study shows that polymeric agents alone or combinations ofpolymeric agents one of which has some surfactant like properties arenot sufficient to achieve good foaming properties in the case ofwater-based vehicles containing large amounts of short chain alcohols.

Polymer alone, surfactant plus polymer and combinations of polymers, oneof which has surfactant like properties all failed to produce a qualityhydro-alcoholic foam. This is a surprising result considering that basedon the prior art, surfactants are known as useful foam boasting agents,especially when used in combination with polymeric agents. It appearsthat high levels of SCA's e.g. ethanol have an apparent defoaming effector destabilizing effect, and thus it is not at all obvious how to obtaingood quality foams with high levels of short chain alcohols.

Example 3 Hydro-Alcoholic Formulations Containing Fatty Alcohols orFatty Acids

The influence of fatty alcohols and fatty acids on the foamingproperties of hydro-alcoholic formulations was studied. As described inTable 3a below, formulation 4 containing a carbomer polymer and amixture behenyl and stearyl alcohol did not give a foam but a bubblyliquid.

Surprisingly, however, the use of a cellulose-based polymer such asHydroxypropyl methylcellulose in combination with behenyl and stearylalcohol improves the foaming properties and good quality foam wasproduced as shown in formulation 6. So hydroxypropyl methylcelluloseappears to be preferred over a pH sensitive expandable polymer likecarbopol.

Unexpectedly, it has also been discovered that the use of ceto-stearylalcohol (a mixture of cetyl and stearyl alcohol) substantially improvesthe foaming properties of hydro-alcoholic formulations. For example,formulation 15 which contains a combination of carbomer and ceto-stearylalcohol unexpectedly gives an excellent quality breakable foam that hasa collapse time of about 90 sec at 36° C., whereas 4 (combination ofcarbomer, behenyl and stearyl alcohol) merely gives a bubbly liquid.

The use of cellulose-based polymers such as hydroxypropylmethylcellulose or hydroxypropyl cellulose further improves the foamingproperties of hydro-alcoholic formulations. Formulation 16 whichcontains a combination of Hydroxypropyl methylcellulose and ceto-stearylalcohol provides an excellent quality breakable foam that has a collapsetime of about 120 sec at 36° C. As observed, the single-phaseformulations 10A and 10B, combinations of Hydroxypropyl cellulose andceto-stearyl alcohol are particularly successful and can provideexcellent quality breakable foams that have a collapse time of more than120 sec at 36° C.

We have thus discovered that certain polymers and certain fatty alcoholsare hydro-alcoholic composition booster stabilizing agents of particularimportance for hydro-alcoholic formulations. In certain embodiments thefatty alcohols have a carbon chain of between 14 to 18 carbons. As canbe observed from the investigation of fatty alcohols and polymersdetailed below in Tables 3a-3c the preferable polymers arecellulose-based polymers and preferable fatty alcohols have a saturatedcarbon chain of between 16 to 18 carbons. These two composition boosterstabilizing agents can work synergistically to provide breakable foamsof excellent quality which are stable at 36° C. (i.e they do notbreakdown rapidly on being exposed to a surface or a space at 36° C.).

TABLE 3a Formulations containing fatty alcohols Formulation 4 6 15 1610A 10B % w/w % w/w % w/w % w/w % w/w % w/w Ingredient Ethanol 51.8051.80 51.50 51.50 51.90 50.20 Purified water 40.00 40.00 40.90 40.9038.30 40.20 Propylene glycol 5.00 — 5.00 — 5.00 5.00 Glycerin — 5.00 —5.00 — — Hydroxypropyl — — — — 3.00 1.50 cellulose Hydroxypropyl — 0.50— 0.50 — — methylcellulose Carbomer 974 0.40 — 0.40 — — —Triethanolamine 0.10 — 0.10 — — — Behenyl alcohol 1.10 1.10 — — — —Stearyl alcohol 0.60 0.60 — — — — Ceto-stearyl — — 2.00 2.00 1.70 3.00alcohol Citric acid 0.40 0.40 0.07 0.07 0.07 0.07 Sodium citrate 0.600.60 0.03 0.03 0.03 0.03 Total 100.00 100.00 100.00 100.00 100.00 100.00Propellant AP-70 8.00 8.00 8.00 8.00 8.00 8.00 Results Foam Quality PoorGood Excellent Excellent Excellent Excellent Collapse Time N/A N/A 90120 >180 120 at 36° C. (sec) Product Clarity No No No Yes Yes Yes

TABLE 3b Additional results for Formulation 10B Foam pH (diluted 1:5)3.40 Foam Density (g/mL) 0.096 Microscopic observation no crystalsStability after centrifugation at 3K, 10 min Homogeneous Stability aftercentrifugation at 10K, 10 min Homogeneous Pre-foam formulation viscosityat 10 rpm (cP) 319 Foam Hardness (grams) 24.53 Mean foam bubble size(micrometers) 62

An additional study was conducted on the influence of the carbon chainlength of fatty alcohol and fatty acids on parameters such as foamquality. As described in Table 3c below, good quality foams can beobtained with combinations of polymer and certain fatty acids or certainfatty alcohols. For example formulation 55 containing a combination ofHydroxypropyl cellulose and stearic acid gave a good quality foam,whereas formulation 61 containing Hydroxypropyl cellulose and isostearicacid only resulted in a bubbly liquid. Without being bound by any theorythe isostearic acid which is non linear and liquid in contrast tostearic acid being linear and solid and may generate some sterichindrance and lower viscosity. Thus, the present invention is notlimited to fatty alcohols and fatty alcohol combinations but includesalso the use of fatty acids and fatty acid combinations as stabilizingagents in hydro-alcoholic foams or in combination with fatty alcohols(see e.g. example 11). The formulations were surprisingly successful inthe absence of a customary surfactant.

To evaluate the possible importance of the carbon chain length on thefoaming properties of hydro-alcoholic formulations, several fattyalcohols containing from 14 to 22 carbons were used in combination withpolymer to create foams. Surprisingly, formulations with fatty alcoholcomprising 14 (myristyl alcohol) or 22 (behenyl alcohol) carbons ontheir own failed to generate a quality foam and only produced bubblyliquids, as shown in the results for formulations 56 and 59. However, afatty alcohol having a carbon chain length of about 16 to about 18 gavefoams of quality in combination with Hydroxypropyl cellulose. Forexample, cetyl alcohol (C16) provided fairly good quality foam andstearyl alcohol gave good quality foams, as shown in formulations 57 and58. Significantly, and unexpectedly, the combination of cetyl alcoholand stearyl alcohol is synergistic and results in excellent quality foamas shown in the results for formulation 60, which contains Hydroxypropylcellulose and cetostearyl alcohol, a mixture of 50% cetyl alcohol and50% stearyl alcohol. Such excellent quality foams were not observed inthe examples containing either cetyl alcohol alone or stearyl alcoholalone. [See Tables 3a and c and compare and contrast the foam qualityfor formulations 6, 57, 58 and 60].Thus, we have discovered that acombination of two fatty alcohols having a carbon chain length of about16 to about 18 have a synergistic effect and dramatically enhance thefoaming properties of hydro-alcoholic formulations.

TABLE 3c Formulations containing fatty alcohols and fatty acids ofdifferent carbon chain length Formulation 55 61 56 57 58 59 60 % w/w %w/w % w/w % w/w % w/w % w/w % w/w Ingredient Ethanol 50.00  50.00 50.00  50.00  50.00  50.00  50.00  Water 45.50  45.50  45.50  45.50 45.50  45.50  45.50  Stearic acid (C18) 3.00 — — — — — — Isostearic acid(C18) — 3.00 — — — — — Myristyl alcohol (C14) — — 3.00 — — — — Cetylalcohol (C16) — — — 3.00 — — — Stearyl alcohol (C18) — — — — 3.00 — —Behenyl alcohol (C22) — — — — — 3.00 — Cetostearyl alcohol — — — — — —3.00 (C16 + C18) Hydroxypropyl 1.50 1.50 1.50 1.50 1.50 1.50 1.50cellulose Total 100.00  100.00  100.00  100.00  100.00  100.00  100.00 Propellant AP-70 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Results Foam QualityGood Poor Poor Fairly Good Good Fair Excellent

Example 4 Thermal Stability—Comparative Example

Two foam formulations (Formulation 001 and 10B-9) were compared with afoam formulation from patent, U.S. Pat. No. 6,126,920, Example 1, asdescribed in Table 4a. The foam samples were placed on fingers of a malevolunteer and the thermal stability of each of the foams was assessed bymeasuring the time it takes to melt on the fingers. Foam formulation 001and 10B-9 were thermally stable and did not melt on contact with theskin for more than three minutes, thus providing an easy and convenientapplication for the user of the product. In contrast, the foamformulation from U.S. Pat. No. 6,126,920, Example 1, which is describedas a “quick-breaking” foam, was thermally unstable and quickly liquefiedand melted on contact with the skin within 15 seconds, making theproduct application difficult for the user and causing the drug toabsorb on the fingers, rather than on the intended target site oftreatment. Therefore, it has been found that by combining suitablepolymeric agent with suitable foam adjuvants it is possible to excludethe need for surfactant in hydro alcoholic formulation yet achievingfoams with enhanced thermal stability.

TABLE 4a Comparative example Formulation Sample according to U.S. Pat.No. 6,126,920 001 10B-9 Example 1 Ingredient % w/w % w/w % w/w Ethanol50.20 50.20 57.79 Purified water 41.48 40.20 33.69 Propylene glycol 5.005.00 2.00 Hydroxypropyl cellulose 1.50 1.50 — Cetostearyl alcohol — 3.00— Citric acid 0.07 0.07 0.073 Sodium citrate 0.03 0.03 — Potassiumcitrate — — 0.027 Polysorbate 60 — — 0.40 Octadecan-1-ol (stearyl 0.50 —0.50 alcohol) Cetyl alcohol 1.10 — 1.10 Betamethasone valerate 0.12 0.120.12 Hydrocarbon propellant 8.00 8.00 4.30 (butane/propane/isobutane)Time to 50% melting >3 minutes >3 minutes 15 seconds

Two amended formulations based on foam formulations from patent, U.S.Pat. No. 6,126,920, Example 1 were prepared as described in Table 4b. Afoam Sample according to U.S. Pat. No. 6,126,920 Example 1 withsurfactant but where all the fatty alcohols were removed from thecomposition failed to produce foam. A foam Sample according to U.S. Pat.No. 6,126,920 Example 1 with surfactant and containing 3% cetostearylalcohol produced quality foam. These surprising results emphasize theimportance of including suitable fatty alcohols into hydro-alcoholicfoam formulation

TABLE 4b Comparative example Formulation Sample according to Sampleaccording to U.S. Pat. No. U.S. Pat. No. 6,126,920 Example 1 6,126,920Example 1 with removed fatty with 3% Cetostearyl alcohols alcoholIngredient % w/w % w/w Ethanol 57.79 57.79 Purified water 35.29 32.29Propylene glycol 2.00 2.00 Cetostearyl alcohol — 3.00 Citric acid 0.0730.073 Potassium citrate 0.027 0.027 Polysorbate 60 0.40 0.40Betamethasone valerate 0.12 0.12 Hydrocarbon propellant 4.30 4.30(butane/propane/ isobutane) Total 100.00 100.00 Foam Quality PoorExcellent

Example 5 Stability of a Steroid in Hydro-Alcoholic Formulations

This example illustrates the stability of betamethasone 17 valerate(BMV-17) in two foam compositions, namely 10B9 and 16B as described inTable 5a below. Samples a were stored at 5° C. and 40° C., and theconcentrations of betamethasone 17 valerate and its respectivedegradation product betamethasone 21 valerate (BMV-21) were determinedby UPLC. The stability test results following 3 and 6 months of storageare shown in Table 5b.

TABLE 5a Composition of foam formulation incubated during 3 months and 6months 10B-9 16B Ingredient % w/w % w/w Ethanol 50.20 51.50 Purifiedwater 40.20 40.90 Propylene glycol 5.00 — Glycerin — 5.00 Hydroxypropylcellulose 1.50 — Hydroxypropyl methylcellulose — 0.50 Cetostearylalcohol 3.00 2.00 Citric acid 0.07 0.07 Sodium citrate 0.03 0.03Betamethasone valerate-17 0.12 0.12 Hydrocarbon Propellant AP-70 8.008.00

TABLE 5b Stability results of foam compositions containing betamethasonevalerate-17 Formulation 10-B Formulation 16B Time-point Component % w/w% w/w 3 months at 5° C. BMV-17 0.116 0.120 BMV-21 0.000 0.000 3 monthsat 40° C. BMV-17 0.115 0.118 BMV-21 0.003 0.004 6 months at 5° C. BMV-170.117 0.120 BMV-21 0.000 0.000 6 months at 40° C. BMV-17 0.112 0.113BMV-21 0.006 0.008

The results after 3 months and 6 months at 5° C. show that no measurabledegradation of the active agent or appearance of its degradation productoccurred at this low storage temperature. The accelerated stabilityresults after 3 months and 6 months at 40° C. showed a very minimaldegradation of the active agent in the formulations, the degradationproduct BMV-21 being detected at the low levels of 2-3% at 3months and6-8% at 6 months. Moreover, stability at 40° C. for 6m can be translatedinto an expected stability at room temperature for a year or more. Theformulations herein thus show an ability to withstand extendedaccelerated stability for the steroidal active agent.

Example 6 Hydro-Alcoholic Formulations Containing other Different ActiveIngredients

Several active ingredients (API) were added to formulation 10B in orderto assess the compatibility between the foam and the API. Parameterssuch as foam quality, foam density, collapse time and product claritywere evaluated as described in Table 6a below.

Formulations containing betamethasone valerate, diclofenac sodium,metronidazole, clindamycin phosphate and benzoyl peroxide (BPO) gaverise to breakable foams of excellent quality which were stable at 36° C.with a collapse time of more than 3 minutes. The first four formulationswere clear single phase solutions. The fifth formulation containing BPOwas not clear as BPO is insoluble. Interestingly, diclofenac appeared toincrease foam density. Without being bound to any theory it is expectedthat in order to form a homogenous suspension of BPO a carbomer at a pHwhich at which its expansion is reduced would be included. See sectionon suspensions.

TABLE 6a Formulations containing various active ingredients Formulation10B9 10B1 10B2 10B3 10B7 % w/w % w/w % w/w % w/w % w/w IngredientEthanol 50.20 50.20 50.20 50.20 50.20 Purified water 40.20 40.20 40.2040.20 40.20 Propylene glycol 5.00 5.00 5.00 5.00 5.00 Hydroxypropyl 1.501.50 1.50 1.50 1.50 cellulose Cetostearyl alcohol 3.00 3.00 3.00 3.003.00 Citric acid 0.07 0.07 0.07 0.07 0.07 Sodium citrate 0.03 0.03 0.030.03 0.03 Total 100.00 100.00 100.00 100.00 100.00 Betamethasone 0.12 —— — — valerate Diclofenac sodium — 1.00 — — — Metronidazole — — 0.75 — —Clindamycin — — — 1.00 — phosphate Benzoyl Peroxide — — — — 5.00Propellant AP-70 8.00 8.00 8.00 8.00 8.00 Results Foam Quality ExcellentExcellent Excellent Excellent Excellent Collapse Timeat >180 >180 >180 >180 >180 36° C. (sec) Foam Density 0.096 0.165 0.0740.063 0.067 (g/mL) Product clarity Yes Yes Yes Yes No

Example 7 Hydro-Alcoholic Formulations Containing a Range of EthanolConcentrations

Several formulations were prepared containing different concentrationsof ethanol. Parameters such as foam quality, collapse time, foam densitywere evaluated as described in Table 7a below.

Formulations containing up to 60% ethanol provided breakable foams ofgood to excellent quality, that were stable at 36° C. having collapsetimes of more than 3 minutes. Also surprisingly the carrier withoutethanol provided a good quality foam in the absence of surfactant.However, in the absence of alcohol the importance of polymer isenhanced. Ethanol despite its defoaming and thermolabile properties,unexpectedly improved the foam quality and generated stable breakablefoam contrary to that seen in the prior art.

TABLE 7a Fourmulations containing a range of ethanol concentrationsFormulation 51 51b 50 21 10A 24 % w/w % w/w % w/w % w/w % w/w % w/wIngredient Ethanol — — 20.00 30.00 51.90 60.00 Purified water 95.50 97  75.50 60.20 38.30 30.20 Propylene glycol — — — 5.00 5.00 5.00Hydroxypropyl 1.50 — 1.50 3.00 3.00 3.00 cellulose Cetostearyl 3.00 3.003.00 1.70 1.70 1.70 alcohol Citric acid — — — 0.07 0.07 0.07 Sodiumcitrate — — — 0.03 0.03 0.03 Total 100.00 100.00  100.00 100.00 100.00100.00 Propellant AP-70 8.00 8.00 8.00 8.00 8.00 8.00 Results FoamQuality Good Poor Excellent Excellent Excellent Excellent Collapse Timeat >180 >180 >180 >180 >180 36° C. (sec) Foam Density 0.103 0.063 0.0860.100 0.092

Example 8 Hydro-Alcoholic Formulations Containing Minimal Ingredients

Several ingredients were removed from formulation 10B in order to assessthe contribution of each of them to the foam properties. Parameters suchas foam quality, collapse time and product clarity were evaluated, andresults described in Table 8a.

Foams of excellent quality that were stable at 36° C. were obtained informulations without humectants and without pH buffering agents.However, the presence of a fatty alcohol with the polymer seem to berequired, given that the formulation with hydroxypropyl cellulosepolymer but lacking cetostearyl alcohol did not give foam but a bubblyliquid.

TABLE 8a Formulations containing minimal ingredients Formulation 10B 2729 % w/w % w/w % w/w Ingredient Ethanol 50.20 50.20 50.20 Purified water40.20 45.30 43.20 Propylene glycol 5.00 — 5.00 Hydroxypropyl cellulose1.50 1.50 1.50 Cetostearyl alcohol 3.00 3.00 — Citric acid 0.07 — 0.07Sodium citrate 0.03 — 0.03 Total 100.00 100.00 100.00 Propellant AP-708.00 8.00 8.00 Results Foam Quality Excellent Excellent Poor CollapseTime at 36° C. (sec) 120 >180 — Product clarity Yes Yes Yes

Example 9 Hydro-Alcoholic Formulations Containing Isopropanol

A foam formulation was prepared containing isopropanol (C3H7OH), whichis another example of short chain alcohol. Parameters such as foamquality and collapse time were evaluated. As described in Table 8a, afoam of good quality was obtained in a formulation containingisopropanol.

TABLE 9a Formulation containing isopropanol Formulation 49 % w/wIngredient Isopropanol 50.00 Purified water 45.50 Hydroxypropylcellulose 1.50 Cetostearyl alcohol 3.00 Total 100.00 Propellant AP-708.00 Results Foam Quality Good

So, it follows that the above revelations as to how to achieve a shortterm stable breakable foam that is a foam which is stable upon exposureto body temperature despite the presence of a high level of ethanolshould apply likewise mutatis mutandis to other short chain alcoholssuch as, isopropanol, propanol, butanaol, iso-butanol, t-butanol andpentanol. In one or more embodiments there is provided a short termstable breakable foam formulation comprising one or more short chainalcohols.

Example 10 Stability and Solubility of Mometasone Furoate inHydro-Alcoholic Formulations

This example illustrates the stability and solubility of mometasonefuroate in two foam compositions, namely M009 and M016 as described inTable 10a below. Samples were stored at 40° C., and the concentrationsof mometasone furoate were determined by UPLC. The stability testresults following 1 and 2 months of storage are shown in Table 10b.

TABLE 10a Composition of foam formulation incubated during 3 months M009M016 % w/w % w/w Ingredient Isopropyl alcohol — 40.00 Ethanol 45.00 —Hexylene Glycol 12.00 12.00 Purified Water 32.95 31.00 Propylene Glycol5.00 10.95 Hydroxypropylcellulose 3.00 1.50 Stearyl alcohol — 4.00Cetostearyl alcohol 1.50 — Sodium citrate 0.19 0.19 Citric acid 0.260.26 Mometasone furoate 0.10 0.10 Total 100.00 100.00 Propellant AP708.00 8.00 Results Foam Quality Excellent Good Collapse Time at 36° C.(sec) >180 >180 Solubility of Mometasone Furoate Soluble Soluble Visualinspection Clear solution Clear solution

TABLE 10b Stability results of a foam composition containing Mometasonefuroate Formulation M009 Time point Concentration of Mometasone FuroateT0 0.0990 1 months at 40° C. 0.0976 2 months at 40° C. 0.0979

The results after 1 and 2 months of incubation at 40° C. show a veryminimal degradation of the active agent in the formulations, Theformulations herein thus show an extended accelerated stability of thesteroidal active agent for at least 2 month.

Example 11 Hydro-Alcoholic Formulations Containing Fatty Alcohol andFatty Acids

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing mixtures of fatty alcohol andfatty acids as described in Table 11 below.

TABLE 11 Formulations mixtures of fatty alcohol and fatty acidsFormulation 002 003 004 % w/w % w/w % w/w Ingredient Ethanol 58.0 58.058.0 Purified water 32.0 32.0 32.0 Hydroxypropylcellulose 1.5 1.5 1.5Propylene glycol 6.9 6.9 6.9 Cetyl alcohol 0.8 — — Myristyl alcohol 0.8— — Stearyl alcohol — 0.8 — Stearic acid — 0.8 0.8 Myristic acid — — 0.8Total 100.00 100.00 100.00 AP-70 8.00 8.00 8.00 Results Foam QualityGood Good Good Collapse Time at 36° C. (sec) 55 >180 >180 Foam Density(g/mL) 0.074 0.049 0.189

When 3% cetyl alcohol and 3% myristyl alcohol are used alone inhydro-alcoholic formulations containing a polymeric agent, poor andfairly good foams are obtained respectively, as shown in formulations 56and 57 described in Example 3. Poor foam collapses rapidly. Surprisinglyhowever, when 0.8% myristyl alcohol is combined with 0.8% cetyl alcoholtogether with a polymeric agent, a short term stable breakable foam ofgood quality is achieved having a low density and a collapse time ofabout a minute. So the combination of cetyl and myristyl alcoholtogether with a polymeric agent achieves a synergistic effect.

A breakable foam of good quality with a collapse time in excess of 180seconds and a low density was achieved by the combination of a fattyacid and a fatty alcohol, for example stearic acid and stearyl alcoholor a combination of two fatty acids, for example stearic acid andmyristic acid.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation which provides a short term stable breakable foam with acollapse time of about 60 seconds at 36° C., and containing acombination of two or more fatty alcohols. In one or more embodimentsthe combination is synergistic.

In one or more embodiments, there is provided a hydro-alcoholic foamableformulation which provides a short term stable breakable foam with acollapse time of more than 180 sec at 36° C., and containing acombination of one or more fatty alcohols with one or more fatty acidsor a combination of two or more fatty acids .

Example 12 Hydro-Alcoholic Formulations Containing Different Ratios ofFatty Alcohol

Parameters such as foam quality, collapse time and foam density wereevaluated in foam formulations containing different ratios of cetylalcohol and stearyl alcohol as described in Table 12 below.

TABLE 12 Formulations containing different ratios of fatty alcoholFormulation 005 006 007 % w/w % w/w % w/w Ingredient Ethanol 58.0 58.058.0 Purified water 32.0 32.0 32.0 Hydroxypropylcellulose 1.5 1.5 1.5Propylene glycol 6.9 6.9 6.9 Cetyl alcohol 1.1 0.8 0.5 Stearyl alcohol0.5 0.8 1.1 Total 100.00 100.00 100.00 AP-70 8.00 8.00 8.00 Results FoamQuality Good Excellent Excellent Collapse Time >180 >180 >180 FoamDensity 0.060 0.073 0.059 cetyl:stearyl alcohol ratio 2.2:1 (i.e.11:5)1:1 1:2.2 (i.e.5:11)

In the context of hydro-alcoholic formulations containing a polymericagent, it can be seen that breakable foams of good to excellent qualitywith a collapse time of more than 180 seconds can be obtained by thecombination of different ratios of two fatty alcohols, (in this examplecetyl alcohol and stearyl alcohol). In one or more embodiments, theratio of two fatty alcohols can be optimized in order to improve foamproperties such as foam quality and foam collapse time.

Surprisingly, it appears that the foam quality can be stronglyinfluenced by the ratio of mixtures of fatty alcohols such as cetyl andstearyl alcohol. Formulations having a cetyl:stearyl alcohol ratio ofabout 1:1 to about 5:11 gave breakable foam of excellent quality beingstable by showing a collapse time of 3 minutes at 36° C. However, whenthe ratio of cetyl:stearyl alcohol was about 11:5 good quality foam wasproduced. It was further noted that stearyl alcohol appears to have amore significant role in the synergistic relationship than cetylalcohol.

1. (canceled)
 2. A method of treating a dermatological or mucosaldisorder, comprising applying a composition to a skin surface in need oftreatment for the dermatological or mucosal disorder, said compositioncomprising: one or more antibiotic agents; at least about 50% by weightof a short chain alcohol; a polymeric agent; between about 2% and about50% of at least one organic carrier selected from the group consistingof a polar solvent, a hydrophobic organic carrier, and a mixturethereof; an active herbal extract; a metal; and an antioxidant; whereinthe composition is a surfactant free composition.
 3. The method of claim2, wherein the disorder is selected from an infection, an inflammation,an acne, a rosacea, a psoriasis, an eczema, and an atopic dermatitis. 4.The method of claim 2, wherein the one or more antibiotic agentscomprise a tetracycline antibiotic, or a salt, ion, or complex thereof.5. The method of claim 2, wherein the one or more antibiotic agents areabout 0.1% to about 5% by weight of the composition.
 6. The method ofclaim 5, wherein the one or more antibiotic agents are about 1% byweight of the composition.
 7. The method of claim 5, wherein the one ormore antibiotic agents are about 5% by weight of the composition.
 8. Themethod of claim 2, wherein the antioxidant is about 0.1% to about 10% byweight of the composition.
 9. The method of claim 2, wherein the shortchain alcohol comprises ethanol.
 10. The method of claim 2, wherein theat least one organic carrier comprises a polar solvent.
 11. The methodof claim 10, wherein the polar solvent comprises propylene glycol. 12.The method of claim 2, wherein the polymeric agent comprises a celluloseether.
 13. The method of claim 12, wherein the cellulose ether comprisesa hydroxypropyl cellulose.
 14. The method of claim 10, wherein the polarsolvent is about 5% to about 25% by weight of the composition.
 15. Themethod of claim 11, wherein the polar solvent is about 17% to about 23%by weight of the composition.
 16. The method of claim 4, wherein the oneor more antibiotic agents are present in a therapeutically effectiveconcentration.
 17. The method of claim 2, wherein the polymeric agent isabout 0.1% to about 5% by weight of the composition.
 18. The method ofclaim 2, wherein: the one or more antibiotic agents comprise atetracycline antibiotic, or a salt, ion, or complex thereof; the shortchain alcohol comprises ethanol; the polymeric agent comprises acellulose ether; and the at least one organic carrier comprises a polarsolvent, wherein the polar solvent comprises a glycol.
 19. The method ofclaim 18, wherein: the tetracycline antibiotic is about 0.1% to about 5%by weight of the composition; the cellulose ether is about 0.1% to about5% by weight of the composition; the glycol is about 5% to about 25% byweight of the composition; and the antioxidant is about 0.1% to about10% by weight of the composition.
 20. The method of claim 19, whereinthe tetracycline antibiotic is about 1% by weight of the composition.21. The method of claim 19, wherein the cellulose ether comprises ahydroxypropyl cellulose and the glycol comprises a propylene glycol. 22.The method of claim 19, wherein the glycol is about 17% to about 23% byweight of the composition.
 23. The method of claim 2, further comprisinga liquefied or compressed gas propellant.
 24. A method of treating adermatological or mucosal disorder, comprising applying a composition toa skin surface in need of treatment for the dermatological or mucosaldisorder, said composition comprising: an active agent consisting of anantibiotic; at least about 50% by weight of a short chain alcohol; apolymeric agent; and between about 2% and about 50% of at least oneorganic carrier selected from the group consisting of a polar solvent, ahydrophobic organic carrier, and a mixture thereof; wherein thecomposition comprises no surfactant.
 25. The method of claim 24, whereinthe at least one organic carrier is about 17% to about 23% by weight ofthe composition.
 26. A method of treating a dermatological or mucosaldisorder, comprising applying a non-surfactant carrier composition to asurface in need of treatment for the dermatological or mucosal disorder,said composition comprising: an active agent consisting of anantibiotic; at least about 60% by weight of ethanol; a cellulose ether;a glycol; an active herbal extract; a metal; and an antioxidant; whereinthe non-surfactant carrier composition is surfactant free.
 27. Themethod of claim 26, wherein the glycol comprises propylene glycol. 28.The method of claim 27, wherein the glycol comprises propylene glycolbetween about 17% and about 23% by weight of the composition.
 29. Themethod of claim 26, wherein the antibiotic comprises a tetracyclineantibiotic, or a salt, ion, or complex thereof, and is about 0.1% toabout 5% by weight of the composition; the cellulose ether compriseshydroxypropyl cellulose and is about 0.1% to about 5% by weight of thecomposition; and the glycol comprises propylene glycol and is about 17%to about 23% by weight of the composition.
 30. The method of claim 24,wherein the disorder is acne or rosacea.
 31. The method of claim 26,wherein the disorder is acne or rosacea.
 32. The method of claim 29,wherein the antioxidant is about 0.1% to about 10% by weight of thecomposition.
 33. The method of claim 29, wherein ethanol is at leastabout 65% by weight of the composition.